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Chronic pyelonephritis and renal medullary necrosis
Chronic
Pyelonephritis
and Renal
Medullary
Necrosis
By HARRY Z. MELLINS, M.D.
IGNIFICANT ADVANCES in our understanding of chronic pyelonephritis have been made in the last decade and radiologic investigations have resulted in important observations concerning the pathogenesis of the disease.
S
CHRONIC PYELONEPHRITIS
A working definition, taken from Black with slight modification, is that chronic pyelonephritis represents established and often progressive damage to the kidneys and ureters, initiated and possibly perpetuated by infection of the urinary tract.1 The renal lesion is a chronic interstitial nephritis. It has been emphasized by Kimmelstiel et al.,19 Heptinstall,ls and others that renal biopsy is not a specific test for chronic pyelonephritis for many reasons: (1) Chronic interstitial nephritis has many causes other than bacteria: analgesics, urinary tract obstruction, heavy metals (e.g., lead poisoning), sickle cell hemoglobinopathy, metabolic disorders (e.g., hypercalcemia, gout), and irradiation. (2) The gross anatomic distribution of the interstitial nephritis and its relation to the calices, one of the criteria for the diagnosis of chronic pyelonephritis, cannot be determined from a biopsy specimen. The infection involves one or more collecting ducts in a pyramid and the pathologic changes are confined to the environs of these ducts and the nephrons that drain into them. Adjacent ducts and nephrons are not altered. (3) A normal biopsy cannot exclude the diagnosis of chronic pyelonephritis because the specimen may be taken from an area of normal renal tissue between focal areas of involvement. Pathology
and Pathogenesis
Ureteral lesions are an integral part of the disease. Twenty years ago it was often emphasized that “pyelitis” ultimately progressed to pyelonephritis and that it was important to keep the nephritis ever in mind. The pendulum has moved and now it is the anatomic changes caused by the pyelitis that may be disregarded. Some specimens of chronic pyelonephritis show thickening of the wall of the renal pelvis as an end result of inflammation of the mucosa and submucosa.24 There may be contraction of the pelvis caused by fibrosis, and sometimes deformity caused by focal scarring or incisura formation (Fig. 1). It is worthwhile to recognize these changes, but one should appreciate that they do not cause the renal involvement and do not account for the characteristic clubbing of the involved calix or calices in chronic pyelonephritis. The calix is clubbed because of atrophy and fibrosis of its pyramid and overlying cortex with resultant atrophy and outward retraction of the papilla. Chronic pyelonephritis often begins as an acute urinary tract infection in the newborn, in infancy, or in childhood. It may be hematogenous, particularly in HARRY
Division
292
2. MELLINS, of Diagnostic
M.D.: Professor of Radiology, Haruard Medical School; Director, Radiology, Peter Bent Brigham Hospital, Boston, Mass. 02115. SEMINARSINROENTGENOLOGY,
Vo~.6,No.3
(Ju~~),19’71
CHRONIC
PYELONEPHIUTIS
Fig. L-Chronic pyeA. Retrograde lonephritis.
yelograrn. Contracted, 5 eformed renal pelves bidense right laterally, middle calix wtihout papillary indentation, and marked left caliectasis. B. Nephrotomogram. Focal depression of the right renal outline with loss of renal parenchyma lateral to the middle calix. There is focal scarrin in the medial aspect oH the left upper ole and inferior to the mix dle calix.
infancy when it is equally common in both sexes. It is now believed that after the newborn period, most renal infections originate as cystitis, ascending later to the upper urinary tract. Although the subject has received much study, the mechanisms responsible for infection of the bladder by the usual organisms, most commonly colon bacilli, are not well understood. It is clear, however, that cystitis, once established, often interferes with the closure mechanism of the distal ureter.26 Vesicoureteral reflux constitutes an active mechanism for the conversion of cystitis to pyelitis. Prior to the recognition by Hodson and Edwards of the role of reflux in the pathogenesis of chronic pyelonephritis,ls nonobstructive pyelonephritis was thought to be hematogenous. It is now clear that infection predisposes to reflux and reflux, in turn, causes the stasis and
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Fig. 2.-Pyeloparenchymal reflux. Voiding cystogram demonstrates vesicoureteral reflux iu a 3-yr-old girl with nonobstructive urinary tract infection. Moderate pyelotubular reflux of the lower and someof the middle calices; massive pyelotubular reflux, and segmentalparenchymal opacification of the upper pole.
Fig. 3.-Pyeloparenchymal
reflux. Void-
ing cystogram reveals vesicoureteral reflux in a boy with type III posterior urethral valves. Pyelotubular reflux displays parenchymal opacification of several renal segments.
residual urine on which infection feeds. This is not to say that all cases of reflux result from infection. Undoubtedly there are some people in whom the development of the ureterovesical junction is sufficiently abnormal to permit reflux as a primary disorder.26 The ultimate step in the process, as demonstrated by voiding cystourethrography, is the propulsion of the cystographic contrast material in the bladder urine, from the calices into the collecting ducts and parenchyma of the kidney. A homogeneous nephrogram of segments of the parenchyma is seen (Figs. 2 and 3). In all likelihood the medulla can be inoculated with bacteria in the same way.
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PYELONEPHRITIS
295
Urinary tract infection is about 15 times more frequent in girls than boys. Predominance of infection in women continues until old age, when men with prostatic enlargement often have obstructive pyelonephritis.2 At least 40% of children with urinary tract infection have vesicoureteral reflux demonstrable on voiding cystourethrography.10 In children and adults with radiologically demonstrable chronic pyelonephritis, the incidence of vesicoureteral reflux is 60 to 7O%,l3,24 and the vast majority of these are females. The number with demonstrable organic obstruction of the ureters, bladder, or urethra is exceedingly small, Roentgen Findings The urographic examination should be conducted with great attention to detail. Every attempt should be made to rid the intenstines of gas and fecal matter which will obscure renal outlines and caliceal details. Fluids should be withheld for at least 12 hr except in oliguric renal insufficiency. One-half milliliter of the triiodinated urographic media should be used per pound of body weight and ureteral compression should be employed to assure adequate delineation of the calices. If the patient is in severe renal failure, satisfactory studies can still be achieved if urography is done within I2 hr after dialysis.22 The lowered urea level will eliminate or decrease the urea diuresis which these patients have and usually will enable the kidneys to concentrate the opaque urine adequately. The preliminary plain film and early nephrogram should be carefully assessed for any alteration in renal size or shape. The most common clinically insignificant causes of asymmetry are developmental: ( 1) incomplete medial rotation of the hilar aspect of the kidney, (2) foreshortening of the kidney because of rotation on its transverse axis, (3) enlargement of renal outline because of duplication of the kidney, and (4) adaptation of the lateral border of the left kidney to the medial border of the spleen. It is important to determine whether one or both kidneys is small, as in many cases of chronic pyelonephritis with atrophy, and whether compensatory valuable hypertrophy exists. MoBWs and Hodson et al.14 have furnished standards, if used with an awareness of human variation. In patients with renal failure, bilateral small kidneys indicate a poor prognosis, and may be seen in chronic glomerulonephritis, chronic pyelonephritis, nephrosclerosis, gouty nephropathy, and irradiation. The early nephrogram, taken 30 set to 1 min after injection of the contrast medium, reveals focal areas of scarring of the outer borders of one or both kidneys (Fig. 1B ), which are usually smaller than normal. The parenchyma beneath the scar is narrowed as a result of fibrosis and atrophy, and the base of the calix to this area is usually flat or bulges outward because of papillary atrophy or retraction. If there is almost complete segmental loss of functioning parenchyma, the calix fills in retrograde fashion from the renal pelvis (Fig. 4). Hodson has shown that chronic pyelonephritis can be differentiated from healed renal infarction and back pressure atrophy. 1s Ischemic atrophy generally causes retraction of the renal outline over a long arc and the caliceal cupping
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‘Z. MELLINS
Fig. 4.-Chronic pyelonephritis. A. Excretion urogram; lo-min fihn. All calices are densely opacified and blunted. The pelvis is mildly deformed. Note flat base of the middle calix and absent papilla. B. Two-minute nephrotomogram. Pelvis, upper, and lower calices are faintly seen. The middle pole is not opacified. C. Three-minute nephrotomogram. Passive filling of the middle calix from the renal pelvis. There is essentially complete atrophy of middle zone parenchyma.
CHRONIC
PYELONEPHRITIS
Fig. 5.-Atrophic pyeA. Excretion lonephritis.
urogram. Small right kidwith diminished ney opaque excretion. B. Nephrotomogram. Atrophic scarred right kidney with extrarenal pelvis. Voiding cystourethrogram demonstrated right vesicoureteral reflux.
Fig. fection
6.-Urinary and reflux.
tract
in-
A. Excretion urogram. Borderline dilatation of right ureter. B. Voiding cystourethrogram demonstratesright vesicoureteral reflux. This was not shown on an earlier nonvoiding cystogram.
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Fig. 7.-Bilateral atrophic pyelonephritis. A. Excretion urogram. Slight counterclockwise rotation of left collecting system frequently seen in cases beginning in early childhood. Note convex outer border of right lower calix. B. Nephrotomogram shows deep scarring of right lower pole lateral to clubbed calix; smaller scars of left renal outline. The right kidney has atrophied more than the left.
is maintained, although the calices may be somewhat closer together as a result of loss of renal substance. Back pressure atrophy from previous obstruction of the collecting system causes uniform dilatation and blunting of the calices with uniform thinning of the entire mantle of renal parenchyma. As noted earlier, almost two thirds of the patients with urographic signs of chronic pyelonephritis demonstrate vesicoureteral reflux to the involved kidney on voiding cystourethrography (Fig. 5). Although a dilated ureter often suggests vesicoureteral reflux (Fig. 6), the excretion urogram is not a consistent indicator of its presence. In some patients, urinary tract infection may produce dilatation of the ureters in the absence of vesicoureteral reflux,ls whereas in others the excretory urogram may be entirely normal even though reflux is readily demonstrated by voiding cystourethrography. Severe disease occurring in childhood may result in atrophic pyelonephritis with marked depression in the rate of kidney growth. This may be unilateral or bilateral (Fig. 7). If only one kidney is involved, the opposite normal kidney will undergo hypertrophy (Fig. 8). The results may be striking and the
CHRONIC
PYELONEPHRITIS
299
Fig. S.-Right chronic pyelonephritis with compensatory left hypertrophy. Excretion urogram showsatrophy, cortical scarring, and flattening of papillae on the right. The vertical diameter of the left kidney is increased and there is concentric hypertrophy. enlarged kidney may reach twice normal volume. The ability of the kidney to undergo hypertrophy is greatest in childhood and under the age of 30. It is of interest that a study of kidney size (coronal section area) related to age revealed the average size to be greatest at age 30.17Above this age, the average size slowly decreases with advancing years and the incidence of significant enlargement following contralateral nephrectomy is very small.11,r7 Possibly the slow atrophy and the inability to hypertrophy both mirror renal circulatory changes that begin about age 30. In patients under 30 with hypertension and obvious chronic pyelonephritis in one kidney, the absence of contralateral hypertrophy strongly suggestsbilateral diseaseand indicates that nephrectomy may not be of value. Over 30, absence of contralateral hypertrophy may not be important but its presence may be considered a good sign. Loss of renal substance in chronic pyelonephritis generally leads to a decrease in the length and breadth of the kidney, but this need not be the case. If the renal atrophy is largely manifested as a larger renal sinus, external measurements may remain the same (Fig. 9) and the amount of renal sinus fat increases. This is readily recognized on the abdominal film if gas and fecal matter are not projected over the kidneys, but more easily on tomograms. Urograms generally show elongation of the infundibula and a wider flare of the side walls of the
HARRY
Z. MELLINS
Fig. 9.-Renal sinus lipomatosis. A. Excretion urogram. Left kidney is longer than right, renal pelves are roughly e ual in size and density, 4but left calices and infundibula are not filled. B. Nephrotomogram. Note large, fat filled renal sinus, low volume calices, and narrow elongated infundibula. The left parenchyma1 volume is less than right although total renal size is greater.
calices (Fig. 10). The condition has been called lipomatosis or fibrolipomatosis of the kidney. It is generally considered to be a response to an atrophic renal process, whether of inflammatory, obstructive, or other etiology.
Renal Calculi Chronic pyelonephritis, if accompanied by recurrent urinary tract infection, may lead to a syndrome of renal stone formation, with serious consequences. Scardino et al. reviewed 278 consecutive patients with renal calculus operated upon over a Q-yr period. 2s All patients had pyuria but urine cultures were not routinely done. There were twice as many women with calculi as men. The calculi were simple in 177 patients and branched (staghorn) in 101. Most of the branched calculi consisted of magnesium ammonium phosphate, often
CHRONIC
PYELONEPHRITIS
Fig. IO.-Renal sinus lipomatosis. Nephrotomogram. Bilateral large renal sinuses. Fat compresses infundibula and sides of calices causing bases to flare, particularly on left.
mixed with calcium phosphate or carbonate. This is the usual composition of staghorn calculi that form in infected alkaline urine. Since the calculi were of the type associated with infection and predominated in women, a causal relationship between urinary tract infection and renal calculus disease, especially with branched calculi, was suggested. In a large group of patients with renal stones, Cochran et al. found that 20% met their diagnostic criteria for chronic pyelonephritis by fulfilling three of the following requirements: a convincing history of urinary tract infections, repeated pyuria with positive bacterial cultures in midstream urine specimens, radiologic changes on excretion urography, histologic evidence, and a positive prednisone provocation test.3 A fourth of this group were unable to acidify the urine to a normal degree and were diagnosed as having renal tubular acidosis. In the entire renal stone group, no patient without infection had renal tubular acidosis. The relation between impaired acidifying power, infection, and stone formation was suggested by the course of many of the patients. One patient had infected urine when first seen but could acidify urine to within the normal range. A year later there was an acidification defect and bilateral stones had appeared. Two patients had acidification defects and small stones when first seen; these rapidly grew to staghom calculi in one year. in association with persistent infection. Two others had had bilateral pyelolithotomy followed by rapid recurrence of staghorn calculi in the presence of untreated infection. When these and three other patients had subsequent pyelolithotomy and then were put on chemotherapy, although renal function remained unchanged, stones did not reform during the follow-up period of 6 to 18 mo. The stones were of the mixed calcium phosphate and magnesium ammonium phosphate variety. The predominant infecting organisms were E. coli and Proteus species. How the infection produces the tubular acidification defect remains to be determined. It is presumed to cause chronic distal tubular damage. This is followed by a vicious circle in which chronically alkaline urine promotes stone
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Z. MELLINS
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CHRONICPYELONEPHRITIS
growth, the presence of stone perpetuates the infection, and this, in turn, further damages the distal tubule. The problem of the rapid appearance or reappearance of staghorn calculi in patients with infected urine has been studied in another way by Waterhouse and his group.28 Voiding cystourethrography has revealed ureterovesical reflux on the side of the calculus in 15%of the cases (Fig. 11). The incompetence of the ureterovesical valve may result from relatively recent urinary tract infection or it may be the residuum of infection and chronic pyelonephritis in childhood. The application time of the urine to the stone nidus, which may be a clump of the infecting bacteria, is much longer by virtue of the repeated episodes of vesicoureteral reflux. Evidence from delayed cystography indicates that reflux frequently occurs during resting periods as well as during micturition. The presence of reflux offers another reason for the rapid growth of branched calculi. Conceivably, reflux could contribute to distal tubule damage and the acidification defect, but evidence is needed to support or disprove this view. RENALMEDULLARYNECROSIS
Renal medullary necrosis (renal papillary necrosis, necrotizing papillitis) is a pathologic change that occurs in a number of diseases.In this presentation the expression renal medulla will be used to denote the aggregate of all the renal pyramids, not including the vertical partitions of cortex between them, the columns of Bertin. The papilla is that portion of the apex of the pyramid that projects into the base of the calix. Certain signs and syinptoms frequently associated with papillary necrosis can also be found in many other conditions. The diagnosis is most often made radiologically but it is imperative to remember that radiographs of excellent quality are required, that the roent,gen signs are occasionally difficult to differentiate from normal variation, and that many frank or advanced cases do not cause any radiologic abnormality at all because the necrotic area has not yet disrupted the caliceal mucous membrane.5 Papillary necrosis occurs frequently, is often missed radiologically, and when recognized, often clarifies otherwise puzzling syndromes. Pathology and Pathogen&s A central area near the tip of the papilla, the entire papilla, or most df the pyramid may be greyish yellow in color, friable, and separated from normal medullary tissue by a narrow whitish rim of tissue representing a marginal zone of inflammatory respdnse and granulation tissue. The caliceal mucosa invaginated by the pyramid may be destroyed at the apex of the papilla, involved over its entire length, or disrupted at one or both fornices. Two types of renal medullary necrosis are described. In the medullary type, necrosis begins in the center of the papilla. If the epithelium is disrupted by the process, the necrotic tissue is discharged into the calix and a small central communicating cavity remains. In the papillary type, the entire papilla and overlying caliceal epithelium become necrotic. If sloughing occurs, the fornices are destroyed and the cavity in the pyramid appears as an extension of the
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caliceal lumen. In both types, the necrotic segment may remain in place and sometimes even become calcified. No matter what the inciting agent is, the process most closely resembles ischemic infarction secondary to obstruction of the vasa recta. The arterial supply of a pyramid is furnished mainly by the efferent arterioles of the juxtamedullary glomeruli, the arteriolae rectae, which follow a straight course into the outer part of the medulla and form long capillary nets which extend to the apex of the papillae. The vena rectae drain the capillary nets of the medulla into the arcurate veins which emptv into the interlobar veins. In urinary tract infection, the vasa recta may be occluded by inflammation and edema of the papilla. The conditions in which renal medullary necrosis is found include chronic pyelonephritis, obstructive uropathy, diabetes mellitus, sickle cell hemoglobinopathy, analgesic nephropathy, renal vein thrombosis, and cirrhosis.21 Renal medullary necrosis should be kept in mind in all patients with active urinary tract infection and renal failure, in hematuria and renal colic, and in slowly progressive renal failure with hyposthenuria and diminished ability to acidify the urine. Whether the increased frequency and virulence of infection in uncontrolled diabetes explains the frequency of renal medullary necrosis or whether the high concentration of glucose in the vasa recta induces thrombosis is still debated. In patients with sickle cell trait or disease, any decrease in the already low oxygen tension in the medulla may cause sickling within the vasa recta, followed by thrombosis and papillary necrosis. Between 7 and 13% of black people in the United States have the heterozygous sickle cell trait and rarely suffer from intravascular sickling; 70% of them have hyposthenuria. In the renal medulla, both the interstitial and the intravascular tissues normally have an osmolarity up to four times the plasma level. This causes sickling of both SA and SC cells. The ascending venae rectae are blocked and, when enough are obstructed, concentration of solutes by the countercurrent system cannot occur and hyposthenuria supervenes. Without hyperosmolarity in the medulla above the plasma level, sickling ceases. The life expectancy of patients with sickle cell trait (SA hemoglobin) differs little from the normal.a,r*,27 The mechanism by which the analgesic drugs occlude the vasa recta in man is not known, but there is evidence from animal experiments that it may be a direct effect on the vasa recta. Since some of the derivatives of analgesic pharmaceuticals cause hemolysis, the nephropathy may be like that in sickle cell hemoglobinopathy.20 In 1968, the number of reported cases of analgesic nephropathy was over 18OO.6 The disease is now reported from all parts of the world. The renal symptoms often do not appear until late in the course of the disease. There may be evidence of personality disorder, headache, peptic ulcer, or anemia. The necrotic papillae may be unilateral or bilateral, more often the latter. Hematuria, loin pain, and pyuria without organisms are common. Acidosis, passage of papillae, and hypertension occur in some patients. Diuresis may offer some protection by reducing the concentration of breakdown products in the medulla.4,20
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PYELONEPHRITIS
Fig. le.-Renal medullary necrosis in heterozygous sickle cell disease. Excretion urogram, left kidney, oblique view. Medullary type cavity in the lateral upper calix; dissection along the pyramidal margin of the medial lower calix.
Roentgen Findings Despite extensive renal medullary necrosis, the urographic findings may be normal until separation or sloughing of the necrotic fraction occurs. Decreased size of the kidney and its papillae may be the only detectable abnormality. More difficult to understand are the instances in which histologically proved papillae have been passed in the urine yet the intravenous urogram or retrograde pyelogram appears normal .7,* Conceivably, the cavity is filled with clot or its communication with the calix is blocked by portions of the necrotic tissue. The medullary type of papillary necrosis produces a rounded or broad shallow cavity usually at or near the apex of the papilla (Fig. 12). The fornices are well maintained. If a remnant of necrotic tissue remains in the cavity, it will produce a nonopaque area in the center and a ring shadow will result. Sometimes the anterior and posterior calices at the same level are almost superimposed and may simulate cavity formation, but oblique films will clarify the findings. Sickle cell hemoglobinopathy most frequently causes the medullary type of lesion (Fig. 12). Tuberculosis may produce cavities in the renal papilla which are indistinguishable radiologically from renal medullary necrosis. The papillary type of medullary necrosis (Fig. 13) may present as a fissure extending from the fornix between the lateral aspect of the pyramid and the adjacent tissue. It may resemble a collapsed caliceal diverticulum or an
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Fig. 13.-Renal medullary necrosis from abuse of analgesics. Retrograde pyelogram. Medullary cavities in the papillae of the right lateral upper and left upper calices. Linear dissections in lateral borders of the right superior and inferior middle pyramids. A papillary fragment is seen in a right lateral lower calix. The changes in the left middle and lower calices are indistinguishable from those of chronic pyelonephritis.
Fig. 14.-Renal medullary necrosis in diabetes. Excretion urogram. A ring shadow outlines a sloughed papilla in the caliceal lumen of the right superior calix. The triangular filling defect at the left ureteropelvic junction is also a sloughed papilla. Note the irregular papillary type of cavity continuous with the left superior middle calix, probably the site of origin of the sloughed papilla.
CHRONIC
PYELONEPHRITIS
lary necrosis. A. Excretion urogram, right kidney. Note the dilated calices, the oval filling defect in the renal pelvis, and the irregularly iriangular, large rine shadow in the lower po& (arrow). B. Plain film, 2 yr later. Large calculus mediallv and three calcified pyiamids laterallv.
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HARRYZMELLINS
elongated normal fornix. Usually it is asymmetric. If the papilla has separated but remains in the calix, a ring of contrast material will surround it, often in the shape of a triangle with convex sides (Fig. 14). Passage of the papilla leaves the outer margin of the calix flat or irregularly convex outward. With either shape, the densest portion of the calix is the most peripheral, which is never the case in the normal calix. The late stage of renal papillary necrosis may therefore be indistinguishable from chronic pyelonephritis. Calcification of lesions of the medullary type results in the formation of a calcific nodule near the tip of the papilla (Fig. 15). Papillary or pyramidal necrosis, when calcified, is roughly triangular and conforms to the size of the structure involved (Fig. 16).
REFERENCES 1. Black, D. A. K.: The problem of chronic pyelonephritis. Practitioner 197:593, 1966. 2. Burke, E. C., and Kelalis, P. P.: Recurrent urinary tract infections in children: clinical approach to diagnosis and treatment. Mayo Clin. Proc. 44:489, 1969. 3. Cochran, M., Peacock, M., Smith, D. A., and Nordin, B. E. C.: Renal tubular acidosis of pyelonephritis with renal stone disease. Brit. Med. J. 2:721, 1968. 4. Dawborn, J. K., Fairley, K. F., Kincaid-Smith, P., and King, W. E.: The association of peptic ulceration, chronic renal disease, and analgesic abuse. Quart. J. Med. 35: 69, 1966. 5. Fairley, K. F., and Kincaid-Smith, P.: Renal papillary necrosis with a normal pyelogram. Brit. Med. J. 1:156, 1968. 6. Gault, M. H., Rudwal, T. C., Engles, W. D., and Dossetor, J. B.: Syndrome associated with the abuse of analgesics. Ann. Intern. Med. 68:906, 1968. 7. Harrow, B. R.: Early forms of renal papillary necrosis. Amer. J. Roentgen. 95: 335, 1965. 8. -: Renal papillary necrosis: a critique of pathogenesis. J. Urol. 97:203, 1967. 9. -, Sloane, J. A., and Liebman, N. C.: Roentgenologic demonstration of renal papillary necrosis in sickle-cell trait. New Eng. J. Med. 268:969, 1963.
10. -, -, and Witus, W. S.: A critical examination of bladder neck obstruction in children. J. Urol. 98:613, 1967. 11. Heideman, H. D., and Rosenbaum, H. D.: A study of renal size after contralateral nephrectomy. Radiology 94:599, 1970. 12. Heptinstall, R. H.: Pathology of the Kidney (ed. 1). Boston, Little, Brown, 1966. 13. Hodson, C. J.: The radiological contribution toward the diagnosis of chronic pyelonephritis. Radiology 88:&X57, 1967. 14. -, Drewe, J. A., Karn, M. N., and King, A.: Renal size in normal children: a radiographic study during life. Arch. Dis. Child. 37:616, 1962. 15. -, and Edwards, D.: Chronic pyelonephritis and vesico-ureteric refluz. Clin. Radio]. 11:219, 1960. 16. Hutch, J. A., and Tanagho, E. A.: Etiology of non-occlusive ureteral dilatation. J. Ural. 93:177, 1965. 17. Karn, M. N.: Radiographic measurements of kidney section area. Ann, Hum. Genet. 25:379, 1962. 18. Kay, C. J., Rosenberg, M. A., Fleisher, P., and Small, J.: Renal papillary necrosis in hemoglobin SC disease. Radiology 90:897, 1968. 19. Kimmelstiel, P., Kim, 0. J., Beres, J. A., and Wellmann, K.: Chronic pyelonephritis. Amer. J. Med. 30:589, 1961.
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20. Kincaid-Smith, P.: Analgesic nephropathy and papillary necrosis. Postgrad. Med. J. 44:807, 1968. 21. Longacre, A. M., and Popky, G. L.: Papillary necrosis in patients with cirrhosis: a study of 102 patients. J. Urol. 99:391, 1968. 22. Matalon, R., and Eisinger, R. P.: Successful intravenous pyelography in advanced uremia-visualization in the post-dialytic state. New Eng. J. Med. 282:835, 1970. 23. MO&, H.: Size of normal kidneys. Acta Radiol. 46640, 1956. 24. Rosenheim, M. L.: Problems of
309 chronic pyelonephritis. Brit. Med. J. 1:1433, 1963. 25. Scardino, P. L., Prince, C. L., and Su, C. T.: An aftermath of pyelonephritis. J. Urol. 96516, 1963. 26. Stephens, F. D., and Lenaghan, D.: The anatomical basis and dynamics of vesicoureteral reflux. J. Urol. 87:669, 1962. 27. Vix, V. A.: Urographic demonstration of renal medullary necrosis in hemoglobin SA and SC disease, Radiology 85:320, 1965. 28. Waterhouse, R. K.: Personal communication.
Pyelonephritis
and Renal
Medullary
Necrosis
By HARRY Z. MELLINS, M.D.
IGNIFICANT ADVANCES in our understanding of chronic pyelonephritis have been made in the last decade and radiologic investigations have resulted in important observations concerning the pathogenesis of the disease.
S
CHRONIC PYELONEPHRITIS
A working definition, taken from Black with slight modification, is that chronic pyelonephritis represents established and often progressive damage to the kidneys and ureters, initiated and possibly perpetuated by infection of the urinary tract.1 The renal lesion is a chronic interstitial nephritis. It has been emphasized by Kimmelstiel et al.,19 Heptinstall,ls and others that renal biopsy is not a specific test for chronic pyelonephritis for many reasons: (1) Chronic interstitial nephritis has many causes other than bacteria: analgesics, urinary tract obstruction, heavy metals (e.g., lead poisoning), sickle cell hemoglobinopathy, metabolic disorders (e.g., hypercalcemia, gout), and irradiation. (2) The gross anatomic distribution of the interstitial nephritis and its relation to the calices, one of the criteria for the diagnosis of chronic pyelonephritis, cannot be determined from a biopsy specimen. The infection involves one or more collecting ducts in a pyramid and the pathologic changes are confined to the environs of these ducts and the nephrons that drain into them. Adjacent ducts and nephrons are not altered. (3) A normal biopsy cannot exclude the diagnosis of chronic pyelonephritis because the specimen may be taken from an area of normal renal tissue between focal areas of involvement. Pathology
and Pathogenesis
Ureteral lesions are an integral part of the disease. Twenty years ago it was often emphasized that “pyelitis” ultimately progressed to pyelonephritis and that it was important to keep the nephritis ever in mind. The pendulum has moved and now it is the anatomic changes caused by the pyelitis that may be disregarded. Some specimens of chronic pyelonephritis show thickening of the wall of the renal pelvis as an end result of inflammation of the mucosa and submucosa.24 There may be contraction of the pelvis caused by fibrosis, and sometimes deformity caused by focal scarring or incisura formation (Fig. 1). It is worthwhile to recognize these changes, but one should appreciate that they do not cause the renal involvement and do not account for the characteristic clubbing of the involved calix or calices in chronic pyelonephritis. The calix is clubbed because of atrophy and fibrosis of its pyramid and overlying cortex with resultant atrophy and outward retraction of the papilla. Chronic pyelonephritis often begins as an acute urinary tract infection in the newborn, in infancy, or in childhood. It may be hematogenous, particularly in HARRY
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2. MELLINS, of Diagnostic
M.D.: Professor of Radiology, Haruard Medical School; Director, Radiology, Peter Bent Brigham Hospital, Boston, Mass. 02115. SEMINARSINROENTGENOLOGY,
Vo~.6,No.3
(Ju~~),19’71
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PYELONEPHIUTIS
Fig. L-Chronic pyeA. Retrograde lonephritis.
yelograrn. Contracted, 5 eformed renal pelves bidense right laterally, middle calix wtihout papillary indentation, and marked left caliectasis. B. Nephrotomogram. Focal depression of the right renal outline with loss of renal parenchyma lateral to the middle calix. There is focal scarrin in the medial aspect oH the left upper ole and inferior to the mix dle calix.
infancy when it is equally common in both sexes. It is now believed that after the newborn period, most renal infections originate as cystitis, ascending later to the upper urinary tract. Although the subject has received much study, the mechanisms responsible for infection of the bladder by the usual organisms, most commonly colon bacilli, are not well understood. It is clear, however, that cystitis, once established, often interferes with the closure mechanism of the distal ureter.26 Vesicoureteral reflux constitutes an active mechanism for the conversion of cystitis to pyelitis. Prior to the recognition by Hodson and Edwards of the role of reflux in the pathogenesis of chronic pyelonephritis,ls nonobstructive pyelonephritis was thought to be hematogenous. It is now clear that infection predisposes to reflux and reflux, in turn, causes the stasis and
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Fig. 2.-Pyeloparenchymal reflux. Voiding cystogram demonstrates vesicoureteral reflux iu a 3-yr-old girl with nonobstructive urinary tract infection. Moderate pyelotubular reflux of the lower and someof the middle calices; massive pyelotubular reflux, and segmentalparenchymal opacification of the upper pole.
Fig. 3.-Pyeloparenchymal
reflux. Void-
ing cystogram reveals vesicoureteral reflux in a boy with type III posterior urethral valves. Pyelotubular reflux displays parenchymal opacification of several renal segments.
residual urine on which infection feeds. This is not to say that all cases of reflux result from infection. Undoubtedly there are some people in whom the development of the ureterovesical junction is sufficiently abnormal to permit reflux as a primary disorder.26 The ultimate step in the process, as demonstrated by voiding cystourethrography, is the propulsion of the cystographic contrast material in the bladder urine, from the calices into the collecting ducts and parenchyma of the kidney. A homogeneous nephrogram of segments of the parenchyma is seen (Figs. 2 and 3). In all likelihood the medulla can be inoculated with bacteria in the same way.
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Urinary tract infection is about 15 times more frequent in girls than boys. Predominance of infection in women continues until old age, when men with prostatic enlargement often have obstructive pyelonephritis.2 At least 40% of children with urinary tract infection have vesicoureteral reflux demonstrable on voiding cystourethrography.10 In children and adults with radiologically demonstrable chronic pyelonephritis, the incidence of vesicoureteral reflux is 60 to 7O%,l3,24 and the vast majority of these are females. The number with demonstrable organic obstruction of the ureters, bladder, or urethra is exceedingly small, Roentgen Findings The urographic examination should be conducted with great attention to detail. Every attempt should be made to rid the intenstines of gas and fecal matter which will obscure renal outlines and caliceal details. Fluids should be withheld for at least 12 hr except in oliguric renal insufficiency. One-half milliliter of the triiodinated urographic media should be used per pound of body weight and ureteral compression should be employed to assure adequate delineation of the calices. If the patient is in severe renal failure, satisfactory studies can still be achieved if urography is done within I2 hr after dialysis.22 The lowered urea level will eliminate or decrease the urea diuresis which these patients have and usually will enable the kidneys to concentrate the opaque urine adequately. The preliminary plain film and early nephrogram should be carefully assessed for any alteration in renal size or shape. The most common clinically insignificant causes of asymmetry are developmental: ( 1) incomplete medial rotation of the hilar aspect of the kidney, (2) foreshortening of the kidney because of rotation on its transverse axis, (3) enlargement of renal outline because of duplication of the kidney, and (4) adaptation of the lateral border of the left kidney to the medial border of the spleen. It is important to determine whether one or both kidneys is small, as in many cases of chronic pyelonephritis with atrophy, and whether compensatory valuable hypertrophy exists. MoBWs and Hodson et al.14 have furnished standards, if used with an awareness of human variation. In patients with renal failure, bilateral small kidneys indicate a poor prognosis, and may be seen in chronic glomerulonephritis, chronic pyelonephritis, nephrosclerosis, gouty nephropathy, and irradiation. The early nephrogram, taken 30 set to 1 min after injection of the contrast medium, reveals focal areas of scarring of the outer borders of one or both kidneys (Fig. 1B ), which are usually smaller than normal. The parenchyma beneath the scar is narrowed as a result of fibrosis and atrophy, and the base of the calix to this area is usually flat or bulges outward because of papillary atrophy or retraction. If there is almost complete segmental loss of functioning parenchyma, the calix fills in retrograde fashion from the renal pelvis (Fig. 4). Hodson has shown that chronic pyelonephritis can be differentiated from healed renal infarction and back pressure atrophy. 1s Ischemic atrophy generally causes retraction of the renal outline over a long arc and the caliceal cupping
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Fig. 4.-Chronic pyelonephritis. A. Excretion urogram; lo-min fihn. All calices are densely opacified and blunted. The pelvis is mildly deformed. Note flat base of the middle calix and absent papilla. B. Two-minute nephrotomogram. Pelvis, upper, and lower calices are faintly seen. The middle pole is not opacified. C. Three-minute nephrotomogram. Passive filling of the middle calix from the renal pelvis. There is essentially complete atrophy of middle zone parenchyma.
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Fig. 5.-Atrophic pyeA. Excretion lonephritis.
urogram. Small right kidwith diminished ney opaque excretion. B. Nephrotomogram. Atrophic scarred right kidney with extrarenal pelvis. Voiding cystourethrogram demonstrated right vesicoureteral reflux.
Fig. fection
6.-Urinary and reflux.
tract
in-
A. Excretion urogram. Borderline dilatation of right ureter. B. Voiding cystourethrogram demonstratesright vesicoureteral reflux. This was not shown on an earlier nonvoiding cystogram.
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Fig. 7.-Bilateral atrophic pyelonephritis. A. Excretion urogram. Slight counterclockwise rotation of left collecting system frequently seen in cases beginning in early childhood. Note convex outer border of right lower calix. B. Nephrotomogram shows deep scarring of right lower pole lateral to clubbed calix; smaller scars of left renal outline. The right kidney has atrophied more than the left.
is maintained, although the calices may be somewhat closer together as a result of loss of renal substance. Back pressure atrophy from previous obstruction of the collecting system causes uniform dilatation and blunting of the calices with uniform thinning of the entire mantle of renal parenchyma. As noted earlier, almost two thirds of the patients with urographic signs of chronic pyelonephritis demonstrate vesicoureteral reflux to the involved kidney on voiding cystourethrography (Fig. 5). Although a dilated ureter often suggests vesicoureteral reflux (Fig. 6), the excretion urogram is not a consistent indicator of its presence. In some patients, urinary tract infection may produce dilatation of the ureters in the absence of vesicoureteral reflux,ls whereas in others the excretory urogram may be entirely normal even though reflux is readily demonstrated by voiding cystourethrography. Severe disease occurring in childhood may result in atrophic pyelonephritis with marked depression in the rate of kidney growth. This may be unilateral or bilateral (Fig. 7). If only one kidney is involved, the opposite normal kidney will undergo hypertrophy (Fig. 8). The results may be striking and the
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299
Fig. S.-Right chronic pyelonephritis with compensatory left hypertrophy. Excretion urogram showsatrophy, cortical scarring, and flattening of papillae on the right. The vertical diameter of the left kidney is increased and there is concentric hypertrophy. enlarged kidney may reach twice normal volume. The ability of the kidney to undergo hypertrophy is greatest in childhood and under the age of 30. It is of interest that a study of kidney size (coronal section area) related to age revealed the average size to be greatest at age 30.17Above this age, the average size slowly decreases with advancing years and the incidence of significant enlargement following contralateral nephrectomy is very small.11,r7 Possibly the slow atrophy and the inability to hypertrophy both mirror renal circulatory changes that begin about age 30. In patients under 30 with hypertension and obvious chronic pyelonephritis in one kidney, the absence of contralateral hypertrophy strongly suggestsbilateral diseaseand indicates that nephrectomy may not be of value. Over 30, absence of contralateral hypertrophy may not be important but its presence may be considered a good sign. Loss of renal substance in chronic pyelonephritis generally leads to a decrease in the length and breadth of the kidney, but this need not be the case. If the renal atrophy is largely manifested as a larger renal sinus, external measurements may remain the same (Fig. 9) and the amount of renal sinus fat increases. This is readily recognized on the abdominal film if gas and fecal matter are not projected over the kidneys, but more easily on tomograms. Urograms generally show elongation of the infundibula and a wider flare of the side walls of the
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Fig. 9.-Renal sinus lipomatosis. A. Excretion urogram. Left kidney is longer than right, renal pelves are roughly e ual in size and density, 4but left calices and infundibula are not filled. B. Nephrotomogram. Note large, fat filled renal sinus, low volume calices, and narrow elongated infundibula. The left parenchyma1 volume is less than right although total renal size is greater.
calices (Fig. 10). The condition has been called lipomatosis or fibrolipomatosis of the kidney. It is generally considered to be a response to an atrophic renal process, whether of inflammatory, obstructive, or other etiology.
Renal Calculi Chronic pyelonephritis, if accompanied by recurrent urinary tract infection, may lead to a syndrome of renal stone formation, with serious consequences. Scardino et al. reviewed 278 consecutive patients with renal calculus operated upon over a Q-yr period. 2s All patients had pyuria but urine cultures were not routinely done. There were twice as many women with calculi as men. The calculi were simple in 177 patients and branched (staghorn) in 101. Most of the branched calculi consisted of magnesium ammonium phosphate, often
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Fig. IO.-Renal sinus lipomatosis. Nephrotomogram. Bilateral large renal sinuses. Fat compresses infundibula and sides of calices causing bases to flare, particularly on left.
mixed with calcium phosphate or carbonate. This is the usual composition of staghorn calculi that form in infected alkaline urine. Since the calculi were of the type associated with infection and predominated in women, a causal relationship between urinary tract infection and renal calculus disease, especially with branched calculi, was suggested. In a large group of patients with renal stones, Cochran et al. found that 20% met their diagnostic criteria for chronic pyelonephritis by fulfilling three of the following requirements: a convincing history of urinary tract infections, repeated pyuria with positive bacterial cultures in midstream urine specimens, radiologic changes on excretion urography, histologic evidence, and a positive prednisone provocation test.3 A fourth of this group were unable to acidify the urine to a normal degree and were diagnosed as having renal tubular acidosis. In the entire renal stone group, no patient without infection had renal tubular acidosis. The relation between impaired acidifying power, infection, and stone formation was suggested by the course of many of the patients. One patient had infected urine when first seen but could acidify urine to within the normal range. A year later there was an acidification defect and bilateral stones had appeared. Two patients had acidification defects and small stones when first seen; these rapidly grew to staghom calculi in one year. in association with persistent infection. Two others had had bilateral pyelolithotomy followed by rapid recurrence of staghorn calculi in the presence of untreated infection. When these and three other patients had subsequent pyelolithotomy and then were put on chemotherapy, although renal function remained unchanged, stones did not reform during the follow-up period of 6 to 18 mo. The stones were of the mixed calcium phosphate and magnesium ammonium phosphate variety. The predominant infecting organisms were E. coli and Proteus species. How the infection produces the tubular acidification defect remains to be determined. It is presumed to cause chronic distal tubular damage. This is followed by a vicious circle in which chronically alkaline urine promotes stone
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growth, the presence of stone perpetuates the infection, and this, in turn, further damages the distal tubule. The problem of the rapid appearance or reappearance of staghorn calculi in patients with infected urine has been studied in another way by Waterhouse and his group.28 Voiding cystourethrography has revealed ureterovesical reflux on the side of the calculus in 15%of the cases (Fig. 11). The incompetence of the ureterovesical valve may result from relatively recent urinary tract infection or it may be the residuum of infection and chronic pyelonephritis in childhood. The application time of the urine to the stone nidus, which may be a clump of the infecting bacteria, is much longer by virtue of the repeated episodes of vesicoureteral reflux. Evidence from delayed cystography indicates that reflux frequently occurs during resting periods as well as during micturition. The presence of reflux offers another reason for the rapid growth of branched calculi. Conceivably, reflux could contribute to distal tubule damage and the acidification defect, but evidence is needed to support or disprove this view. RENALMEDULLARYNECROSIS
Renal medullary necrosis (renal papillary necrosis, necrotizing papillitis) is a pathologic change that occurs in a number of diseases.In this presentation the expression renal medulla will be used to denote the aggregate of all the renal pyramids, not including the vertical partitions of cortex between them, the columns of Bertin. The papilla is that portion of the apex of the pyramid that projects into the base of the calix. Certain signs and syinptoms frequently associated with papillary necrosis can also be found in many other conditions. The diagnosis is most often made radiologically but it is imperative to remember that radiographs of excellent quality are required, that the roent,gen signs are occasionally difficult to differentiate from normal variation, and that many frank or advanced cases do not cause any radiologic abnormality at all because the necrotic area has not yet disrupted the caliceal mucous membrane.5 Papillary necrosis occurs frequently, is often missed radiologically, and when recognized, often clarifies otherwise puzzling syndromes. Pathology and Pathogen&s A central area near the tip of the papilla, the entire papilla, or most df the pyramid may be greyish yellow in color, friable, and separated from normal medullary tissue by a narrow whitish rim of tissue representing a marginal zone of inflammatory respdnse and granulation tissue. The caliceal mucosa invaginated by the pyramid may be destroyed at the apex of the papilla, involved over its entire length, or disrupted at one or both fornices. Two types of renal medullary necrosis are described. In the medullary type, necrosis begins in the center of the papilla. If the epithelium is disrupted by the process, the necrotic tissue is discharged into the calix and a small central communicating cavity remains. In the papillary type, the entire papilla and overlying caliceal epithelium become necrotic. If sloughing occurs, the fornices are destroyed and the cavity in the pyramid appears as an extension of the
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caliceal lumen. In both types, the necrotic segment may remain in place and sometimes even become calcified. No matter what the inciting agent is, the process most closely resembles ischemic infarction secondary to obstruction of the vasa recta. The arterial supply of a pyramid is furnished mainly by the efferent arterioles of the juxtamedullary glomeruli, the arteriolae rectae, which follow a straight course into the outer part of the medulla and form long capillary nets which extend to the apex of the papillae. The vena rectae drain the capillary nets of the medulla into the arcurate veins which emptv into the interlobar veins. In urinary tract infection, the vasa recta may be occluded by inflammation and edema of the papilla. The conditions in which renal medullary necrosis is found include chronic pyelonephritis, obstructive uropathy, diabetes mellitus, sickle cell hemoglobinopathy, analgesic nephropathy, renal vein thrombosis, and cirrhosis.21 Renal medullary necrosis should be kept in mind in all patients with active urinary tract infection and renal failure, in hematuria and renal colic, and in slowly progressive renal failure with hyposthenuria and diminished ability to acidify the urine. Whether the increased frequency and virulence of infection in uncontrolled diabetes explains the frequency of renal medullary necrosis or whether the high concentration of glucose in the vasa recta induces thrombosis is still debated. In patients with sickle cell trait or disease, any decrease in the already low oxygen tension in the medulla may cause sickling within the vasa recta, followed by thrombosis and papillary necrosis. Between 7 and 13% of black people in the United States have the heterozygous sickle cell trait and rarely suffer from intravascular sickling; 70% of them have hyposthenuria. In the renal medulla, both the interstitial and the intravascular tissues normally have an osmolarity up to four times the plasma level. This causes sickling of both SA and SC cells. The ascending venae rectae are blocked and, when enough are obstructed, concentration of solutes by the countercurrent system cannot occur and hyposthenuria supervenes. Without hyperosmolarity in the medulla above the plasma level, sickling ceases. The life expectancy of patients with sickle cell trait (SA hemoglobin) differs little from the normal.a,r*,27 The mechanism by which the analgesic drugs occlude the vasa recta in man is not known, but there is evidence from animal experiments that it may be a direct effect on the vasa recta. Since some of the derivatives of analgesic pharmaceuticals cause hemolysis, the nephropathy may be like that in sickle cell hemoglobinopathy.20 In 1968, the number of reported cases of analgesic nephropathy was over 18OO.6 The disease is now reported from all parts of the world. The renal symptoms often do not appear until late in the course of the disease. There may be evidence of personality disorder, headache, peptic ulcer, or anemia. The necrotic papillae may be unilateral or bilateral, more often the latter. Hematuria, loin pain, and pyuria without organisms are common. Acidosis, passage of papillae, and hypertension occur in some patients. Diuresis may offer some protection by reducing the concentration of breakdown products in the medulla.4,20
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Fig. le.-Renal medullary necrosis in heterozygous sickle cell disease. Excretion urogram, left kidney, oblique view. Medullary type cavity in the lateral upper calix; dissection along the pyramidal margin of the medial lower calix.
Roentgen Findings Despite extensive renal medullary necrosis, the urographic findings may be normal until separation or sloughing of the necrotic fraction occurs. Decreased size of the kidney and its papillae may be the only detectable abnormality. More difficult to understand are the instances in which histologically proved papillae have been passed in the urine yet the intravenous urogram or retrograde pyelogram appears normal .7,* Conceivably, the cavity is filled with clot or its communication with the calix is blocked by portions of the necrotic tissue. The medullary type of papillary necrosis produces a rounded or broad shallow cavity usually at or near the apex of the papilla (Fig. 12). The fornices are well maintained. If a remnant of necrotic tissue remains in the cavity, it will produce a nonopaque area in the center and a ring shadow will result. Sometimes the anterior and posterior calices at the same level are almost superimposed and may simulate cavity formation, but oblique films will clarify the findings. Sickle cell hemoglobinopathy most frequently causes the medullary type of lesion (Fig. 12). Tuberculosis may produce cavities in the renal papilla which are indistinguishable radiologically from renal medullary necrosis. The papillary type of medullary necrosis (Fig. 13) may present as a fissure extending from the fornix between the lateral aspect of the pyramid and the adjacent tissue. It may resemble a collapsed caliceal diverticulum or an
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Fig. 13.-Renal medullary necrosis from abuse of analgesics. Retrograde pyelogram. Medullary cavities in the papillae of the right lateral upper and left upper calices. Linear dissections in lateral borders of the right superior and inferior middle pyramids. A papillary fragment is seen in a right lateral lower calix. The changes in the left middle and lower calices are indistinguishable from those of chronic pyelonephritis.
Fig. 14.-Renal medullary necrosis in diabetes. Excretion urogram. A ring shadow outlines a sloughed papilla in the caliceal lumen of the right superior calix. The triangular filling defect at the left ureteropelvic junction is also a sloughed papilla. Note the irregular papillary type of cavity continuous with the left superior middle calix, probably the site of origin of the sloughed papilla.
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lary necrosis. A. Excretion urogram, right kidney. Note the dilated calices, the oval filling defect in the renal pelvis, and the irregularly iriangular, large rine shadow in the lower po& (arrow). B. Plain film, 2 yr later. Large calculus mediallv and three calcified pyiamids laterallv.
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elongated normal fornix. Usually it is asymmetric. If the papilla has separated but remains in the calix, a ring of contrast material will surround it, often in the shape of a triangle with convex sides (Fig. 14). Passage of the papilla leaves the outer margin of the calix flat or irregularly convex outward. With either shape, the densest portion of the calix is the most peripheral, which is never the case in the normal calix. The late stage of renal papillary necrosis may therefore be indistinguishable from chronic pyelonephritis. Calcification of lesions of the medullary type results in the formation of a calcific nodule near the tip of the papilla (Fig. 15). Papillary or pyramidal necrosis, when calcified, is roughly triangular and conforms to the size of the structure involved (Fig. 16).
REFERENCES 1. Black, D. A. K.: The problem of chronic pyelonephritis. Practitioner 197:593, 1966. 2. Burke, E. C., and Kelalis, P. P.: Recurrent urinary tract infections in children: clinical approach to diagnosis and treatment. Mayo Clin. Proc. 44:489, 1969. 3. Cochran, M., Peacock, M., Smith, D. A., and Nordin, B. E. C.: Renal tubular acidosis of pyelonephritis with renal stone disease. Brit. Med. J. 2:721, 1968. 4. Dawborn, J. K., Fairley, K. F., Kincaid-Smith, P., and King, W. E.: The association of peptic ulceration, chronic renal disease, and analgesic abuse. Quart. J. Med. 35: 69, 1966. 5. Fairley, K. F., and Kincaid-Smith, P.: Renal papillary necrosis with a normal pyelogram. Brit. Med. J. 1:156, 1968. 6. Gault, M. H., Rudwal, T. C., Engles, W. D., and Dossetor, J. B.: Syndrome associated with the abuse of analgesics. Ann. Intern. Med. 68:906, 1968. 7. Harrow, B. R.: Early forms of renal papillary necrosis. Amer. J. Roentgen. 95: 335, 1965. 8. -: Renal papillary necrosis: a critique of pathogenesis. J. Urol. 97:203, 1967. 9. -, Sloane, J. A., and Liebman, N. C.: Roentgenologic demonstration of renal papillary necrosis in sickle-cell trait. New Eng. J. Med. 268:969, 1963.
10. -, -, and Witus, W. S.: A critical examination of bladder neck obstruction in children. J. Urol. 98:613, 1967. 11. Heideman, H. D., and Rosenbaum, H. D.: A study of renal size after contralateral nephrectomy. Radiology 94:599, 1970. 12. Heptinstall, R. H.: Pathology of the Kidney (ed. 1). Boston, Little, Brown, 1966. 13. Hodson, C. J.: The radiological contribution toward the diagnosis of chronic pyelonephritis. Radiology 88:&X57, 1967. 14. -, Drewe, J. A., Karn, M. N., and King, A.: Renal size in normal children: a radiographic study during life. Arch. Dis. Child. 37:616, 1962. 15. -, and Edwards, D.: Chronic pyelonephritis and vesico-ureteric refluz. Clin. Radio]. 11:219, 1960. 16. Hutch, J. A., and Tanagho, E. A.: Etiology of non-occlusive ureteral dilatation. J. Ural. 93:177, 1965. 17. Karn, M. N.: Radiographic measurements of kidney section area. Ann, Hum. Genet. 25:379, 1962. 18. Kay, C. J., Rosenberg, M. A., Fleisher, P., and Small, J.: Renal papillary necrosis in hemoglobin SC disease. Radiology 90:897, 1968. 19. Kimmelstiel, P., Kim, 0. J., Beres, J. A., and Wellmann, K.: Chronic pyelonephritis. Amer. J. Med. 30:589, 1961.
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20. Kincaid-Smith, P.: Analgesic nephropathy and papillary necrosis. Postgrad. Med. J. 44:807, 1968. 21. Longacre, A. M., and Popky, G. L.: Papillary necrosis in patients with cirrhosis: a study of 102 patients. J. Urol. 99:391, 1968. 22. Matalon, R., and Eisinger, R. P.: Successful intravenous pyelography in advanced uremia-visualization in the post-dialytic state. New Eng. J. Med. 282:835, 1970. 23. MO&, H.: Size of normal kidneys. Acta Radiol. 46640, 1956. 24. Rosenheim, M. L.: Problems of
309 chronic pyelonephritis. Brit. Med. J. 1:1433, 1963. 25. Scardino, P. L., Prince, C. L., and Su, C. T.: An aftermath of pyelonephritis. J. Urol. 96516, 1963. 26. Stephens, F. D., and Lenaghan, D.: The anatomical basis and dynamics of vesicoureteral reflux. J. Urol. 87:669, 1962. 27. Vix, V. A.: Urographic demonstration of renal medullary necrosis in hemoglobin SA and SC disease, Radiology 85:320, 1965. 28. Waterhouse, R. K.: Personal communication.