- Email: [email protected]
The Riddle of Randall’s Plaques
Vol. 114, Oct obe r Print ed in U.S.A.
THE JOURNAL Of UROLOGY
Copyright© 1975 by The Williams & Wilkin s Co.
THE RIDDLE OF RANDALL'S PLAQUES EDWIN L. PRIEN, SR. *
From the Laboratory for Ston e Research , Ne wto n, Mussachusetts
ABSTRACT
Randall described a pre-calculus lesion of the renal papilla in the 1930s and this was substantiated by others during the next decade and then largely ignored. This insignificant subepithelial calcification of the renal papilla, Randall 's plaque type I, becomes the nucleus of at least 15 per cent of calcium oxalate calculi, as demonstrated by apatite nuclei existing in papillary depressions on the external stone surface. Cross section study of the stone demonstrates the peripheral nucleus with eccentric lamination postulating a mural origin. Contrariwise, study of the stone developing upon a nucleus originating in the papillary ducts (without producing obstruction) or out in the calix demonstrates a central nucleus surrounded by concentric laminations or lack of a mural origin, the more common type of calcium oxalate stone structure. Obstruction of the papillary ducts by hyperexcretion of stone salt may result in anemic infarction and sloughing of the apex of the papilla. Data concerning the prevalence of Randall's plaques in the population have been reviewed. Evidence of the incidence of calcium oxalate calculi that have developed upon Randall's plaques has been presented. A plea for further study of the pathology of the renal papilla has been voiced. The pathogenesis of calcium oxalate urinary stone remains a mystery despite intensive clinical and investigative study. In 1968 Smith stated, "Epidemiologic data have failed to elucidate stone pathogenesis. It is curious that stones have attracted relatively little investigative attention in view of their importance. This is perhaps not without precedent for interface disorders lodged uneasily between a surgical subspeciality and the metabolic congeries of internal medicine." 1 In 1971 Haggitt and Pitcock pointed out that there is no widely accepted theory of the factors involved in stone formation despite Randall's observations, made nearly 40 years ago, that subepithelial calcifications in the renal papilla gave rise to stones 2 and this was confirmed by others. However, interest in these early observations declined. Possibly this lack of interest stemmed from the fact that nearly all of the earlier observations (except Randall's earlier papers) were in the urologic literature and could have escaped wide notice. Haggitt and Pitcock, who are pathologists, have confirmed Randall's observations. In addition, an intimate optical study of the structure of calculi under the polarizing microscope has supplied hard factual data suggesting that a large percentage of primary calcium oxalate calculi have Accepted for publication March 14, 1975. Editor's note. An exhibit on this subject was displayed at the annual meeting of the American Urological Association, Miami Beach, Florida, Mav 11- 15. 197fi. * Requests for reprints: 81 Wyman St., New ton , Massachusetts 02168.
an asymmetric structure postulating a mural origin from a surface, presumably the caliceal surface of the renal papilla, in accordance with Randall's findings. The study of how stones are formed may possibly serve to shed some light on why they are formed and prompts this review of a paradoxical situation in which only meager support for Randall's theory comes from the autopsy table. STRUCTURE AND INCIDENCE OF RANDALL'S PLAQUES
In the 1930s Randall published a series of papers in which he depicted the early development of renal calculi within and upon the renal papill~. 3 • • He was interested in discovering the pre-calculus lesion. In a study of kidneys removed at autopsy and carefully dissected he found a lesion, usually 1 or 2 mm. in dimensions, upon the renal papilla usually developing as an insignificant subepithelial plaque but extratubular in origin. This lesion was described as a cream-colored area near the tip of the papilla or on the slope away from the tip. Sometimes there were several lesions on the same papilla and several papillae in the same kidney might be involved. On microscopic study the lesion was found to be a plaque of calcium salts deposited in the interstitial tissue of the renal papilla and definitely not intra tubular. Microchemical studies showed it to be composed of calcium carbonate and calcium phosphate (now recognized as carbonate apatite). 5 In places rings of calcium salt were deposited in the basement membrane of the collecting tubule and represented the precursor of the plaque. If the interstitial lesion was located just 500
t
RIDDLE OF RANDALL'S PLAQUES
beneath the epithelium of the papill a there might be desquamation , resulting in exposure of the lesion to the concentrated urine of the calix where it could act as a nucleus, followed by deposition of calcium oxalate. With deposition of successive layers of calcium oxalate upon this nucleus a stone could be formed which might eventually tear loose and become free in the calix . Histologic study of these lesions showed no evidence of infection. Randall described difficulty in the study of the crystalline material in the intrapapillary lesions of the renal papilla . An opportunity to discuss this with him in 1938 and to recommend polarization microscopy for this purpose was enthusiastically received. 6 In 1,154 pairs of kidneys removed at necropsy at 2 Philadelphia hospitals between December 1935 and December 1938 Randall found calcium salt deposition on 1 or more papillae in 19.6 per cent of the kidneys, either unilateral or bilateral, and in 65 individuals a primary renal calculus was observed growing upon and attached to the papilla.• In a study from 1 hospital of 678 consecutive autopsies in which age was correlated with the presence of the lesion, a primary plaque was found in 102 cases ( 15 per cent) , of which two-thirds were in individuals more than 50 years old.• A second pre-calculus lesion discovered by Randall consisted of intratubular inspissation of the terminal portions of the collecting tubules and papillary ducts by calcium salts. Infection was present in about half of the cases , possibly secondary in nature . This is Randall 's type II lesion and may be associated with excessive urinary supersaturation of stone salt. He found it to be much less common than the type I lesion. 3 A number of investigators subsequently studied the renal papilla in consecutive autopsies and produced numerical data concerning the percentage of papillary plaques which approximate Randall's figures (see table) . Histologic study revealed the plaques as occurring in subepithelial interstitial tissue extratubularly and also intratubularly . They were twice as common in male as in female patients and more common in patients more than 50 years old . They were usually composed of calcium phosphate (apatite), less commonly of calcium oxalate and extremely rarely of uric acid . Rosenow found bacteria histologically in twoIn cidence by dec ades in which papillary calc iu m plaques and calculi were found macroscopically-678 autopsies (Randall' s series ) Age
(yrs.) 10- 19 20-29 30- 39 40- 49 50- 59 60-69 70- 79 80- 89
Auto ps ies
Plaques No. (%)
27 41 79 94 124 142 130 4l
l (3.71 4 (9. 71 11 (I 3.91 18 ( l9 .l I 14(11.21 29 (20 .41 21 (1 6. l ) 4 (9 71
Stones No .( %)
2 (4.8) 2 (2.~I 3 (~ .I I :J (2.41 4 (2.81
7 (;, ,:l )
501
thirds of the cases but without evidence of active infection . 7 Posey found Randall's plaques in 35.7 per cent of his cases in the 50 to 60-year age group and 1 or 2 mm. caliceal calculi in 59 per cent of the cases with papillary lesions . 8 However, only 6 of the patients ever had symptoms of stone disease. From his data he suggested that primary stone disease may be quite common but symptomatic stone disease is relatively rare because many tiny calculi are passed without producing symptoms . Vermooten's study in South Africa consisted of kidneys removed at autopsy at the South African Medico-Legal Laboratories, 55 per cent of which had been removed from healthy people who had suffered sudden death and 45 per cent who were hospital patients . Sixty per cent were Bantu, 26 per cent were Caucasian and 7.7 per cent were of mixed origin. Plaques were found in 17.2 per cent of the whites but in only 4.3 per cent of the Bantu in whom, however, calculus disease is extremely rare.•. 1 ° Kj0lhede and Lassen found calculi in the calices of 14 kidneys, in 6 of which there were no plaques, and believed that Randall's plaques are therefore of no great significance in the genesis of calculi . 11 Anderson described calcifications first appearing within the epithelial cells of the renal tubules . The cells become necrotic and the calcification distends the renal tubules and then disintegrates to form a calcified nidus or seeding point which acts as a nucleus when it is expelled to the renal pelvis. He thought that Randall's plaques were a rare source of stone formation. 12 Haggitt and Pitcock , recent investigators, found tiny calcium deposits in the interstitium and basement membrane of the medulla in all of the kidneys of 100 autopsies . However, papillae of only 23 kidneys contained Randall 's plaques. 2 In an attempt to find correlations between the presence of Randall 's plaques and primary calcium stone formation as reported in the literature, we have found some contradictions. That Randall's plaques exist is certain and careful study of renal papillae by most investigators seems to have established that they are precursors of calcium stone formation. A seemingly major problem is that the majority of the plaques apparently occur in subjects more than 50 years old, whereas the clinical stone age is in the previous 3 decades of life . Several investigators who have voiced this problem and who have found calculi in calices in which no lesions of the papilla were found have assumed that all calculi must originate from nuclei developing in the supersaturated urine of the calix or excreted by the tubules as pointed out by Anderson. 12 In a personal study in the late 1940s of more than 100 unopened kidneys only 1 example of a calcium oxalate calculus attached to the renal papilla was found . Typical plaques were found upon the papillae of 13 kidneys (fig. 1) . The age of the decedents was not considered and may account for the relatively low frequency of plaques as compared to
t
502
PRIEN
D"'
A and B, typical Randall's plaques upon summit of excised human renal papilla. Overlying epithelium is still partially intact. C, more advanced lesion in which plaques are completely exposed to urine of calix. (Scale in FIG. 1.
millimeters.) D, sagittal section near apex of papilla with suhepithelial apatite plaque eroding overlying caliceal epithelium. Reduced from x 180.
previously cited studies. However, I have subse<1uently received a number of excised renal papillae bearing plaques and stones from residents in pathology who knew of my interest in the subject. Urologists infrequently do nephrectomies on patients whose kidneys might show Randall's plaques and this has been my experience . Nevertheless, routine observations at the autopsy table have not provided strong support for Randall's theory. STUDY OF STRUCTURE OF CALCIUM OXALATE CALCULI
Probably the most important support comes from intimate study of large numbers of small ureteral calculi. Optical study reveals that many have no regularity of structure. However, many calcium oxalate calculi do have regular structure, permitting recognition of a nucleus and sequential growth as manifested by laminations or change in composition. Some may be composed of calcium oxalate throughout or exhibit a central nucleus composed of apatite or rarely of uric acid. Origin is by excretion from the papillary ducts as a nidus or
by development in the calix. Growth may result by concentric lamination or in such a manner that origin from the surface of the papilla is improbable (fig. 2, C to F). There is no lesion of the papilla and, therefore, no Randall's plaque to be discovered at autopsy. Personal study by low power dissection plus identification under the polarizing microscope has shown that 15 per cent of thousands of calcium oxalate ureteral calculi do not have a central but an eccentric structure. On cross section these stones show evidence of a layered growth originating from a peripheral nucleus located in a depression on the external surface of the stone (figs. 2 and 3). 13- 1 • The nucleus is commonly composed of apatite (fig. 4). occasionally of calcium oxalate or it may be missing, revealing a void where it had been . With growth of the stone it separates from the papilla , according to Randall 's study, and becomes a free stone in the calix . This sequence is depicted in figure 2, G to M. Study of calcium oxalate calculi , whatever their mode of origin, has shown that calcium oxalate monohydrate is the
503
RIDDLE OF RANDALL'S PLAQUES
./- )
~ -fl fl:)
~
R
t
L
Q K
t
~ ~~,
J
I
OE
H
D
t Al1 ~ ~ t
Ji]IMi
p
0
N
FIG. 2. Diagrammatic representation of ren a l papill a depicting development of calculi. A, papillary ducts. C to F, common mode of development from tubule to calix. G to M, development of asymmetric calcium oxalate stone from subepithelial Randall 's plaque type I. N to R , obstruction of papillary ducts (only 1 shown) by stone salt followed by anemic infarction and sloughing of adjacent perit ubular tissue, type II lesion.
primarily deposited hydrate of calcium oxalate and many such stones will have an outer layer of calcium oxalate dihydrate crystals completely en veloping the stone. However, many of the stones developing from a Randall's plaque and having an external (eccentric) nucleus will have a thin peripheral layer of calcium oxalate dihydrate covering the free surface of the stone, while the surface of the stone impinging upon the papillary surface as at figure 2, K will be free of calcium oxalate dihydrate deposition. This, with the evidence of bits of papillary tissue still adherent to the stone would seem to offer strong support for the mural origin of the stone. The 2 stones in figure 5 appear to have developed from Randall's plaques and are composed of calcium oxalate monohydrate on apatite nuclei . While the majority of calculi develop from nuclei excreted from the renal tubules and produce no lesion of the papilla as has been described, the obstruction of the tubules by stone salts as a result of excessive supersaturation (or hyperexcretion as stated by Randall) may result in a type II lesion as depicted in figure 2, N to R . It undoubtedly is identical with the calcium infarct of the older pathologists and it may produce the snow capped papilla of Vermooten when the entire papilla is involved. In figure 2 the series N to R represents the production of a type II lesion by the experimen tal production of hyperoxaluria in pyridoxine defi-
cient rats with obstruction of the papillary ducts by impacted calcium oxalate crystals, followed by anemic infarction, necrosis a nd sloughing of the adjacent peritubular t issues (fig. 6). The 2 human calcium oxalate stones of figure 7 probably represent such sloughed calcareous infarcts of the renal papilla, type II lesions . The striated structure of the nuclei appears to be the result of calcification in involved tubules which sloughed when the infarct and its attached stone separated from the papilla. Such calculi are quite uncommon. Kj0lhede and Lassen described necrotic holes without epithelial covering upon the papilla, apparently the result of such sloughing infarcts. 11 Since the type II lesion is the result of hyperexcretion and not of interstitial calcification it could be composed of calcium oxalate, calcium phosphate or uric acid as Posey has stated. 8 Whether such a stone will always have a recognizable nucleus is unknown . This lesion is quite uncommon and our experience is too limited . Elliot, using low power dissection of ureteral calculi and the polarizing microscope, found that approximately half of 150 ureteral calculi exhibited a papillary depression, suggesting a former attachment to the tip of t he renal papilla and composed of calcium oxalate. 16• 1 7 However, he apparently did not correlate the presence of the papillary depression with cross section study of the stone, a necessary step to show that eccentric growth origi-
t:
504
PRIEN
CM
D
C I
I
I'
•
I
i l
I
FIG. 3. A and B, cross sections of calcium oxalate calculi with peripheral apatite nuclei originating as Randall's plaques but with some overgrowth of stone salt deposited upon nucleus after stone separated from papilla but lingered in urinary tract. C and D, calcium oxalate monohydrate calculi (black) with naked apatite nuclei (white). Immediate excretion of stone after it became free of papilla. (Scale in millimeters.) (A and B reprinted with permission from The Williams and Wilkins Co.")
nated from a Randall's plaque. He stated that "the obvious role of the renal papilla in the genesis of calculi seems to have been overlooked". 17 Nordin stated that some calculi have an eccentric structure, suggesting attachment to epithelium but he thought that most stones have a central nucleus. 18 STONE RESEARCH
Present day research is not concerned with a consideration of the Randall's plaque phenomenon but with the concept of stone nucleation, growth and aggregation of crystals and of the urinary inhibitors of these processes. This presupposes that all of the factors involved apply to crystalloids freely excreted into the calix by the papillary ducts but they do not include nucleation by the Randall's plaque. It is not implied that this casts any
doubts on the validity of such stone research to which the author wholeheartedly subscribes. However, it will not explain the pathogenesis of stones developed from Randall's plaques. In fact, 1 of the enigmas of calcium stone disease is why it is frequently not possible to demonstrate excessive urine supersaturation for calcium oxalate in calcium stone formers as compared to normal subjects, while it is regularly present for the other stone species in patients with uric acid, cystine and infected (MgNH,PO,) calculi. Of course the solubility of all of these is considerably influenced by changes in urinary pH, while calcium oxalate solubility is only slightly influenced over the clinical pH range. Is it not possible that transient or more modest degrees of supersaturation with calcium oxalate, which would otherwise pass without
RIDDLE OF RANDALL'S PLAQUES
505
!V{J.tL Cl 'C / l.,, __ LU...:J
FIG. 4. Ca lcium oxalate sto ne with Randall 's plaque nucleus. (Rep r inted with permission from The Williams and Wilkins Co. 13 )
Fie:. !i. Excised human renal papilla depicting 2 sma ll calcium oxalate calcu li formed upon apatite nuclei originat ing as Randall's type I plaques. (Scale in millimeters .) (Reprinted with permission from The Williams and Wilkins Co.'')
clinical event, may be influenced by the presence of Randall's plaques? It has been demonstrated by Elliot and Robertson and their associates that the urine of normal persons is moderately supersaturated with calcium oxalate at various periods of the day . 19 • 20 This is known as the zone of metastability in physical chemistry and calcium oxalate will not precipitate to form stone unless a nucleus is introduced into it. Of course, if marked supersaturation occurs there will be spontaneous precipitation of a nucleus and stone formation. However, in the patient with a Randall 's plaque a nucleus is provided to initiate stone formation and growth in this lower normal level of urinary supersaturation. Apatite can be shown to nucleate calcium oxalate in vitro. 21 The fact that Randall 's plaque nuclei are found only in calcium oxalate calculi underscores the likelihood of such a unique relationship. What is the relative incidence of calculi develop-
ing from Randall's plaques in the individual who has a single or occasional stone , possibly related to over-indulgence in a high calcium or high oxalate food, as compared to the incidence in the idiopathic recurrent stone former during the clinical stone age? We do not know. A study of the structure of calculi correlated with the age and sex of the patient and recurrence rate may tell us. This is being carried out. Possibly the examination of the interior of the kidney at operation with the new fiberoptic nephroscope with visualization of the calices may supply information on the incidence of Randall 's plaques in the stone patient. While we know the incidence of plaques in the clinical stone age from autopsy statistics, we do not know the incidence in stone-forming persons. Various investigators have found the incidence of plaques to be from 17 to 35 per cent in the population at large at autopsy, which is much more common than the incidence of recurrent stone formers in the general
506
PRIEN
FIG. 6. Cross section of renal papilla of rat shows experimentally produced calcium oxalate calculus upon apex of papilla. Impaction of papillary duct by inspissated urinary salts followed by anemic infarction, necrosis and sloughing of adjacent area with stone formation . Type II lesion of Randall. Reduced from x 150. (Reprinted with permission from The Williams and Wilkins Co.")
kidney lesions of Randall's plaques and Dr. Frederick J. Parker, Jr. provided kidneys removed at necropsy at Mallory Institute of Pathology, Boston City Hospital and slides and pathologic description of tissue in figure 6. REFERENCES
FIG. 7. Calcium oxalate calculi with striated nuclei composed of calcified renal tubules impacted with apatite and involved in adjacent anemic infarction with sloughing. Probable type II lesion of Randall involving papillary ducts on apex of renal papilla. (Scale in millimeters.)
population. This is evidence that other factors in stone causation clearly exist. May not a Randall's plaque nucleus in a stone contribute to an understanding of recurrent calcium oxalate formation in approximately normal urine in which the concepts of physical chemistry and the unsolved nature of the crystallization inhibitors may not be entirely adequate in supplying an explanation? It is hoped that a renewed attack on the pathology of the renal papilla coupled with the present day study of the crystal chemistry of stone formation may help to solve the riddle of urinary calculus disease. Dr. Rodger C. Haggitt provided some of the
1. Smith, L. H ., Jr.: Symposium on stones. Introduction. Books in the running brooks, sermons in stone. Amer. J. Med., 45: 649, 1968. 2. Haggitt, R. C. and Pitcock, J. A.: Renal medullary calcifications: a light and electron microscopic study. J. Urol. , 106: 342, 1971. 3. Randall, A.: The etiology of primary renal calculus. In: VII Congress of the International Society of Urology, p. 186, 1939. 4. Randall, A.: Papillary pathology as a precursor of primary renal calculus. J. Urol., 44: 580, 1940. 5. Prien, E. L. and Frondel, C.: Studies in urolithiasis: I. The composition of urinary calculi. J. Urol., 57: 949, 1947. 6. Prien, E. L.: The use of polarized light in the analysis of calculi and in the study of crystals in tissue: a preliminary report on the method employed. J . Urol., 45: 765, 1941. 7. Rosenow, E. C. , Jr.: Renal calculi: a study of papillary calcification. J. Urol., 44: 19, 1940. 8. Posey, L. C.: Urinary concretions. II. A study of the primary calculous lesions. J. Urol. , 48: 300, 1942. 9. Vermooten, V.: The incidence and significance of the deposition of calcium plaques in the renal papilla as observed in the Caucasian and Negro (Bantu) populations in South Africa. J . Urol., 46: 193, 1941. 10. Vermooten, V. : The origin and development in the renal papilla of Randall's calcium plaques. J . Urol., 48: 27, 1942. 11. Kjcplhede, K. T. H. and Lassen, H. K.: The signifi-
507
RIDDLE OF RANDALL'S PLAQUES
12.
13.
14.
15.
16.
cance of Randall's papillary lesions in the causation of renal calculi. J. Urol., 47: 45, 1942. Anderson, C. K.: Renal histological changes in stone formers and non-stone formers. In: Renal Stone Research Symposium . Edited by A. Hodgkinson and B. E. C. Nordin. Baltimore: The Williams & Wilkins Co., p . 133, 1968. Prien, E . L.: Studies in urolithiasis : II. Relationships between pathogenesis, structure and composition of calculi. J. Urol. , 61: 821. 1949. Prien, E. L.: Studies in urolithiasis: ill. Physicochemical principles in stone formation and prevention . J. Urol. , 73: 627, 1955. Prien, E. L. and Prien, E. L., Jr.: Composition and structure of urinary stone. Amer. J. Med .. 45: 654, 1968. Elliot, J. S. : Structure and composition of urinary calculi. J . Urol., 109: 82, 1973.
17. Elliot, J. S. : Optical analysis of urinary calculi: the value of low power dissection. In: Urinary Calculi. Recent Advances in Aetiology , Stone Structure and Treatment. Proceedings of the International Symposium on Renal Stone Research . Edited by L. Cifuentes Delatte, A. Rapedo and A. Hodgkinson . !\lew York: S. Karger, p. 216, 1973. 18. Nordin, B. E. C.: Urinary tract calculi. In: Metabolic Bone and Stone Disease . Baltimore: The Williams & Wilkins Co., p. 233, 1973. 19. Elliot, J. S . and Ribeiro, M.: Calcium oxalate solubility in urine: the state of relative saturation. Invest. Urol., 5: 239, 1967. 20. Robertson , W. G., Peacock , M. and :-,.;ordin. B. E .: Activity products in stone-forming and non-stoneforming urine. Clin. Sci., 34: 579, 1968. 21. Smith, L . H. and Meyer, J.: Personal communication.
t
THE JOURNAL Of UROLOGY
Copyright© 1975 by The Williams & Wilkin s Co.
THE RIDDLE OF RANDALL'S PLAQUES EDWIN L. PRIEN, SR. *
From the Laboratory for Ston e Research , Ne wto n, Mussachusetts
ABSTRACT
Randall described a pre-calculus lesion of the renal papilla in the 1930s and this was substantiated by others during the next decade and then largely ignored. This insignificant subepithelial calcification of the renal papilla, Randall 's plaque type I, becomes the nucleus of at least 15 per cent of calcium oxalate calculi, as demonstrated by apatite nuclei existing in papillary depressions on the external stone surface. Cross section study of the stone demonstrates the peripheral nucleus with eccentric lamination postulating a mural origin. Contrariwise, study of the stone developing upon a nucleus originating in the papillary ducts (without producing obstruction) or out in the calix demonstrates a central nucleus surrounded by concentric laminations or lack of a mural origin, the more common type of calcium oxalate stone structure. Obstruction of the papillary ducts by hyperexcretion of stone salt may result in anemic infarction and sloughing of the apex of the papilla. Data concerning the prevalence of Randall's plaques in the population have been reviewed. Evidence of the incidence of calcium oxalate calculi that have developed upon Randall's plaques has been presented. A plea for further study of the pathology of the renal papilla has been voiced. The pathogenesis of calcium oxalate urinary stone remains a mystery despite intensive clinical and investigative study. In 1968 Smith stated, "Epidemiologic data have failed to elucidate stone pathogenesis. It is curious that stones have attracted relatively little investigative attention in view of their importance. This is perhaps not without precedent for interface disorders lodged uneasily between a surgical subspeciality and the metabolic congeries of internal medicine." 1 In 1971 Haggitt and Pitcock pointed out that there is no widely accepted theory of the factors involved in stone formation despite Randall's observations, made nearly 40 years ago, that subepithelial calcifications in the renal papilla gave rise to stones 2 and this was confirmed by others. However, interest in these early observations declined. Possibly this lack of interest stemmed from the fact that nearly all of the earlier observations (except Randall's earlier papers) were in the urologic literature and could have escaped wide notice. Haggitt and Pitcock, who are pathologists, have confirmed Randall's observations. In addition, an intimate optical study of the structure of calculi under the polarizing microscope has supplied hard factual data suggesting that a large percentage of primary calcium oxalate calculi have Accepted for publication March 14, 1975. Editor's note. An exhibit on this subject was displayed at the annual meeting of the American Urological Association, Miami Beach, Florida, Mav 11- 15. 197fi. * Requests for reprints: 81 Wyman St., New ton , Massachusetts 02168.
an asymmetric structure postulating a mural origin from a surface, presumably the caliceal surface of the renal papilla, in accordance with Randall's findings. The study of how stones are formed may possibly serve to shed some light on why they are formed and prompts this review of a paradoxical situation in which only meager support for Randall's theory comes from the autopsy table. STRUCTURE AND INCIDENCE OF RANDALL'S PLAQUES
In the 1930s Randall published a series of papers in which he depicted the early development of renal calculi within and upon the renal papill~. 3 • • He was interested in discovering the pre-calculus lesion. In a study of kidneys removed at autopsy and carefully dissected he found a lesion, usually 1 or 2 mm. in dimensions, upon the renal papilla usually developing as an insignificant subepithelial plaque but extratubular in origin. This lesion was described as a cream-colored area near the tip of the papilla or on the slope away from the tip. Sometimes there were several lesions on the same papilla and several papillae in the same kidney might be involved. On microscopic study the lesion was found to be a plaque of calcium salts deposited in the interstitial tissue of the renal papilla and definitely not intra tubular. Microchemical studies showed it to be composed of calcium carbonate and calcium phosphate (now recognized as carbonate apatite). 5 In places rings of calcium salt were deposited in the basement membrane of the collecting tubule and represented the precursor of the plaque. If the interstitial lesion was located just 500
t
RIDDLE OF RANDALL'S PLAQUES
beneath the epithelium of the papill a there might be desquamation , resulting in exposure of the lesion to the concentrated urine of the calix where it could act as a nucleus, followed by deposition of calcium oxalate. With deposition of successive layers of calcium oxalate upon this nucleus a stone could be formed which might eventually tear loose and become free in the calix . Histologic study of these lesions showed no evidence of infection. Randall described difficulty in the study of the crystalline material in the intrapapillary lesions of the renal papilla . An opportunity to discuss this with him in 1938 and to recommend polarization microscopy for this purpose was enthusiastically received. 6 In 1,154 pairs of kidneys removed at necropsy at 2 Philadelphia hospitals between December 1935 and December 1938 Randall found calcium salt deposition on 1 or more papillae in 19.6 per cent of the kidneys, either unilateral or bilateral, and in 65 individuals a primary renal calculus was observed growing upon and attached to the papilla.• In a study from 1 hospital of 678 consecutive autopsies in which age was correlated with the presence of the lesion, a primary plaque was found in 102 cases ( 15 per cent) , of which two-thirds were in individuals more than 50 years old.• A second pre-calculus lesion discovered by Randall consisted of intratubular inspissation of the terminal portions of the collecting tubules and papillary ducts by calcium salts. Infection was present in about half of the cases , possibly secondary in nature . This is Randall 's type II lesion and may be associated with excessive urinary supersaturation of stone salt. He found it to be much less common than the type I lesion. 3 A number of investigators subsequently studied the renal papilla in consecutive autopsies and produced numerical data concerning the percentage of papillary plaques which approximate Randall's figures (see table) . Histologic study revealed the plaques as occurring in subepithelial interstitial tissue extratubularly and also intratubularly . They were twice as common in male as in female patients and more common in patients more than 50 years old . They were usually composed of calcium phosphate (apatite), less commonly of calcium oxalate and extremely rarely of uric acid . Rosenow found bacteria histologically in twoIn cidence by dec ades in which papillary calc iu m plaques and calculi were found macroscopically-678 autopsies (Randall' s series ) Age
(yrs.) 10- 19 20-29 30- 39 40- 49 50- 59 60-69 70- 79 80- 89
Auto ps ies
Plaques No. (%)
27 41 79 94 124 142 130 4l
l (3.71 4 (9. 71 11 (I 3.91 18 ( l9 .l I 14(11.21 29 (20 .41 21 (1 6. l ) 4 (9 71
Stones No .( %)
2 (4.8) 2 (2.~I 3 (~ .I I :J (2.41 4 (2.81
7 (;, ,:l )
501
thirds of the cases but without evidence of active infection . 7 Posey found Randall's plaques in 35.7 per cent of his cases in the 50 to 60-year age group and 1 or 2 mm. caliceal calculi in 59 per cent of the cases with papillary lesions . 8 However, only 6 of the patients ever had symptoms of stone disease. From his data he suggested that primary stone disease may be quite common but symptomatic stone disease is relatively rare because many tiny calculi are passed without producing symptoms . Vermooten's study in South Africa consisted of kidneys removed at autopsy at the South African Medico-Legal Laboratories, 55 per cent of which had been removed from healthy people who had suffered sudden death and 45 per cent who were hospital patients . Sixty per cent were Bantu, 26 per cent were Caucasian and 7.7 per cent were of mixed origin. Plaques were found in 17.2 per cent of the whites but in only 4.3 per cent of the Bantu in whom, however, calculus disease is extremely rare.•. 1 ° Kj0lhede and Lassen found calculi in the calices of 14 kidneys, in 6 of which there were no plaques, and believed that Randall's plaques are therefore of no great significance in the genesis of calculi . 11 Anderson described calcifications first appearing within the epithelial cells of the renal tubules . The cells become necrotic and the calcification distends the renal tubules and then disintegrates to form a calcified nidus or seeding point which acts as a nucleus when it is expelled to the renal pelvis. He thought that Randall's plaques were a rare source of stone formation. 12 Haggitt and Pitcock , recent investigators, found tiny calcium deposits in the interstitium and basement membrane of the medulla in all of the kidneys of 100 autopsies . However, papillae of only 23 kidneys contained Randall 's plaques. 2 In an attempt to find correlations between the presence of Randall 's plaques and primary calcium stone formation as reported in the literature, we have found some contradictions. That Randall's plaques exist is certain and careful study of renal papillae by most investigators seems to have established that they are precursors of calcium stone formation. A seemingly major problem is that the majority of the plaques apparently occur in subjects more than 50 years old, whereas the clinical stone age is in the previous 3 decades of life . Several investigators who have voiced this problem and who have found calculi in calices in which no lesions of the papilla were found have assumed that all calculi must originate from nuclei developing in the supersaturated urine of the calix or excreted by the tubules as pointed out by Anderson. 12 In a personal study in the late 1940s of more than 100 unopened kidneys only 1 example of a calcium oxalate calculus attached to the renal papilla was found . Typical plaques were found upon the papillae of 13 kidneys (fig. 1) . The age of the decedents was not considered and may account for the relatively low frequency of plaques as compared to
t
502
PRIEN
D"'
A and B, typical Randall's plaques upon summit of excised human renal papilla. Overlying epithelium is still partially intact. C, more advanced lesion in which plaques are completely exposed to urine of calix. (Scale in FIG. 1.
millimeters.) D, sagittal section near apex of papilla with suhepithelial apatite plaque eroding overlying caliceal epithelium. Reduced from x 180.
previously cited studies. However, I have subse<1uently received a number of excised renal papillae bearing plaques and stones from residents in pathology who knew of my interest in the subject. Urologists infrequently do nephrectomies on patients whose kidneys might show Randall's plaques and this has been my experience . Nevertheless, routine observations at the autopsy table have not provided strong support for Randall's theory. STUDY OF STRUCTURE OF CALCIUM OXALATE CALCULI
Probably the most important support comes from intimate study of large numbers of small ureteral calculi. Optical study reveals that many have no regularity of structure. However, many calcium oxalate calculi do have regular structure, permitting recognition of a nucleus and sequential growth as manifested by laminations or change in composition. Some may be composed of calcium oxalate throughout or exhibit a central nucleus composed of apatite or rarely of uric acid. Origin is by excretion from the papillary ducts as a nidus or
by development in the calix. Growth may result by concentric lamination or in such a manner that origin from the surface of the papilla is improbable (fig. 2, C to F). There is no lesion of the papilla and, therefore, no Randall's plaque to be discovered at autopsy. Personal study by low power dissection plus identification under the polarizing microscope has shown that 15 per cent of thousands of calcium oxalate ureteral calculi do not have a central but an eccentric structure. On cross section these stones show evidence of a layered growth originating from a peripheral nucleus located in a depression on the external surface of the stone (figs. 2 and 3). 13- 1 • The nucleus is commonly composed of apatite (fig. 4). occasionally of calcium oxalate or it may be missing, revealing a void where it had been . With growth of the stone it separates from the papilla , according to Randall 's study, and becomes a free stone in the calix . This sequence is depicted in figure 2, G to M. Study of calcium oxalate calculi , whatever their mode of origin, has shown that calcium oxalate monohydrate is the
503
RIDDLE OF RANDALL'S PLAQUES
./- )
~ -fl fl:)
~
R
t
L
Q K
t
~ ~~,
J
I
OE
H
D
t Al1 ~ ~ t
Ji]IMi
p
0
N
FIG. 2. Diagrammatic representation of ren a l papill a depicting development of calculi. A, papillary ducts. C to F, common mode of development from tubule to calix. G to M, development of asymmetric calcium oxalate stone from subepithelial Randall 's plaque type I. N to R , obstruction of papillary ducts (only 1 shown) by stone salt followed by anemic infarction and sloughing of adjacent perit ubular tissue, type II lesion.
primarily deposited hydrate of calcium oxalate and many such stones will have an outer layer of calcium oxalate dihydrate crystals completely en veloping the stone. However, many of the stones developing from a Randall's plaque and having an external (eccentric) nucleus will have a thin peripheral layer of calcium oxalate dihydrate covering the free surface of the stone, while the surface of the stone impinging upon the papillary surface as at figure 2, K will be free of calcium oxalate dihydrate deposition. This, with the evidence of bits of papillary tissue still adherent to the stone would seem to offer strong support for the mural origin of the stone. The 2 stones in figure 5 appear to have developed from Randall's plaques and are composed of calcium oxalate monohydrate on apatite nuclei . While the majority of calculi develop from nuclei excreted from the renal tubules and produce no lesion of the papilla as has been described, the obstruction of the tubules by stone salts as a result of excessive supersaturation (or hyperexcretion as stated by Randall) may result in a type II lesion as depicted in figure 2, N to R . It undoubtedly is identical with the calcium infarct of the older pathologists and it may produce the snow capped papilla of Vermooten when the entire papilla is involved. In figure 2 the series N to R represents the production of a type II lesion by the experimen tal production of hyperoxaluria in pyridoxine defi-
cient rats with obstruction of the papillary ducts by impacted calcium oxalate crystals, followed by anemic infarction, necrosis a nd sloughing of the adjacent peritubular t issues (fig. 6). The 2 human calcium oxalate stones of figure 7 probably represent such sloughed calcareous infarcts of the renal papilla, type II lesions . The striated structure of the nuclei appears to be the result of calcification in involved tubules which sloughed when the infarct and its attached stone separated from the papilla. Such calculi are quite uncommon. Kj0lhede and Lassen described necrotic holes without epithelial covering upon the papilla, apparently the result of such sloughing infarcts. 11 Since the type II lesion is the result of hyperexcretion and not of interstitial calcification it could be composed of calcium oxalate, calcium phosphate or uric acid as Posey has stated. 8 Whether such a stone will always have a recognizable nucleus is unknown . This lesion is quite uncommon and our experience is too limited . Elliot, using low power dissection of ureteral calculi and the polarizing microscope, found that approximately half of 150 ureteral calculi exhibited a papillary depression, suggesting a former attachment to the tip of t he renal papilla and composed of calcium oxalate. 16• 1 7 However, he apparently did not correlate the presence of the papillary depression with cross section study of the stone, a necessary step to show that eccentric growth origi-
t:
504
PRIEN
CM
D
C I
I
I'
•
I
i l
I
FIG. 3. A and B, cross sections of calcium oxalate calculi with peripheral apatite nuclei originating as Randall's plaques but with some overgrowth of stone salt deposited upon nucleus after stone separated from papilla but lingered in urinary tract. C and D, calcium oxalate monohydrate calculi (black) with naked apatite nuclei (white). Immediate excretion of stone after it became free of papilla. (Scale in millimeters.) (A and B reprinted with permission from The Williams and Wilkins Co.")
nated from a Randall's plaque. He stated that "the obvious role of the renal papilla in the genesis of calculi seems to have been overlooked". 17 Nordin stated that some calculi have an eccentric structure, suggesting attachment to epithelium but he thought that most stones have a central nucleus. 18 STONE RESEARCH
Present day research is not concerned with a consideration of the Randall's plaque phenomenon but with the concept of stone nucleation, growth and aggregation of crystals and of the urinary inhibitors of these processes. This presupposes that all of the factors involved apply to crystalloids freely excreted into the calix by the papillary ducts but they do not include nucleation by the Randall's plaque. It is not implied that this casts any
doubts on the validity of such stone research to which the author wholeheartedly subscribes. However, it will not explain the pathogenesis of stones developed from Randall's plaques. In fact, 1 of the enigmas of calcium stone disease is why it is frequently not possible to demonstrate excessive urine supersaturation for calcium oxalate in calcium stone formers as compared to normal subjects, while it is regularly present for the other stone species in patients with uric acid, cystine and infected (MgNH,PO,) calculi. Of course the solubility of all of these is considerably influenced by changes in urinary pH, while calcium oxalate solubility is only slightly influenced over the clinical pH range. Is it not possible that transient or more modest degrees of supersaturation with calcium oxalate, which would otherwise pass without
RIDDLE OF RANDALL'S PLAQUES
505
!V{J.tL Cl 'C / l.,, __ LU...:J
FIG. 4. Ca lcium oxalate sto ne with Randall 's plaque nucleus. (Rep r inted with permission from The Williams and Wilkins Co. 13 )
Fie:. !i. Excised human renal papilla depicting 2 sma ll calcium oxalate calcu li formed upon apatite nuclei originat ing as Randall's type I plaques. (Scale in millimeters .) (Reprinted with permission from The Williams and Wilkins Co.'')
clinical event, may be influenced by the presence of Randall's plaques? It has been demonstrated by Elliot and Robertson and their associates that the urine of normal persons is moderately supersaturated with calcium oxalate at various periods of the day . 19 • 20 This is known as the zone of metastability in physical chemistry and calcium oxalate will not precipitate to form stone unless a nucleus is introduced into it. Of course, if marked supersaturation occurs there will be spontaneous precipitation of a nucleus and stone formation. However, in the patient with a Randall 's plaque a nucleus is provided to initiate stone formation and growth in this lower normal level of urinary supersaturation. Apatite can be shown to nucleate calcium oxalate in vitro. 21 The fact that Randall 's plaque nuclei are found only in calcium oxalate calculi underscores the likelihood of such a unique relationship. What is the relative incidence of calculi develop-
ing from Randall's plaques in the individual who has a single or occasional stone , possibly related to over-indulgence in a high calcium or high oxalate food, as compared to the incidence in the idiopathic recurrent stone former during the clinical stone age? We do not know. A study of the structure of calculi correlated with the age and sex of the patient and recurrence rate may tell us. This is being carried out. Possibly the examination of the interior of the kidney at operation with the new fiberoptic nephroscope with visualization of the calices may supply information on the incidence of Randall 's plaques in the stone patient. While we know the incidence of plaques in the clinical stone age from autopsy statistics, we do not know the incidence in stone-forming persons. Various investigators have found the incidence of plaques to be from 17 to 35 per cent in the population at large at autopsy, which is much more common than the incidence of recurrent stone formers in the general
506
PRIEN
FIG. 6. Cross section of renal papilla of rat shows experimentally produced calcium oxalate calculus upon apex of papilla. Impaction of papillary duct by inspissated urinary salts followed by anemic infarction, necrosis and sloughing of adjacent area with stone formation . Type II lesion of Randall. Reduced from x 150. (Reprinted with permission from The Williams and Wilkins Co.")
kidney lesions of Randall's plaques and Dr. Frederick J. Parker, Jr. provided kidneys removed at necropsy at Mallory Institute of Pathology, Boston City Hospital and slides and pathologic description of tissue in figure 6. REFERENCES
FIG. 7. Calcium oxalate calculi with striated nuclei composed of calcified renal tubules impacted with apatite and involved in adjacent anemic infarction with sloughing. Probable type II lesion of Randall involving papillary ducts on apex of renal papilla. (Scale in millimeters.)
population. This is evidence that other factors in stone causation clearly exist. May not a Randall's plaque nucleus in a stone contribute to an understanding of recurrent calcium oxalate formation in approximately normal urine in which the concepts of physical chemistry and the unsolved nature of the crystallization inhibitors may not be entirely adequate in supplying an explanation? It is hoped that a renewed attack on the pathology of the renal papilla coupled with the present day study of the crystal chemistry of stone formation may help to solve the riddle of urinary calculus disease. Dr. Rodger C. Haggitt provided some of the
1. Smith, L. H ., Jr.: Symposium on stones. Introduction. Books in the running brooks, sermons in stone. Amer. J. Med., 45: 649, 1968. 2. Haggitt, R. C. and Pitcock, J. A.: Renal medullary calcifications: a light and electron microscopic study. J. Urol. , 106: 342, 1971. 3. Randall, A.: The etiology of primary renal calculus. In: VII Congress of the International Society of Urology, p. 186, 1939. 4. Randall, A.: Papillary pathology as a precursor of primary renal calculus. J. Urol., 44: 580, 1940. 5. Prien, E. L. and Frondel, C.: Studies in urolithiasis: I. The composition of urinary calculi. J. Urol., 57: 949, 1947. 6. Prien, E. L.: The use of polarized light in the analysis of calculi and in the study of crystals in tissue: a preliminary report on the method employed. J . Urol., 45: 765, 1941. 7. Rosenow, E. C. , Jr.: Renal calculi: a study of papillary calcification. J. Urol., 44: 19, 1940. 8. Posey, L. C.: Urinary concretions. II. A study of the primary calculous lesions. J. Urol. , 48: 300, 1942. 9. Vermooten, V.: The incidence and significance of the deposition of calcium plaques in the renal papilla as observed in the Caucasian and Negro (Bantu) populations in South Africa. J . Urol., 46: 193, 1941. 10. Vermooten, V. : The origin and development in the renal papilla of Randall's calcium plaques. J . Urol., 48: 27, 1942. 11. Kjcplhede, K. T. H. and Lassen, H. K.: The signifi-
507
RIDDLE OF RANDALL'S PLAQUES
12.
13.
14.
15.
16.
cance of Randall's papillary lesions in the causation of renal calculi. J. Urol., 47: 45, 1942. Anderson, C. K.: Renal histological changes in stone formers and non-stone formers. In: Renal Stone Research Symposium . Edited by A. Hodgkinson and B. E. C. Nordin. Baltimore: The Williams & Wilkins Co., p . 133, 1968. Prien, E . L.: Studies in urolithiasis : II. Relationships between pathogenesis, structure and composition of calculi. J. Urol. , 61: 821. 1949. Prien, E. L.: Studies in urolithiasis: ill. Physicochemical principles in stone formation and prevention . J. Urol. , 73: 627, 1955. Prien, E. L. and Prien, E. L., Jr.: Composition and structure of urinary stone. Amer. J. Med .. 45: 654, 1968. Elliot, J. S. : Structure and composition of urinary calculi. J . Urol., 109: 82, 1973.
17. Elliot, J. S. : Optical analysis of urinary calculi: the value of low power dissection. In: Urinary Calculi. Recent Advances in Aetiology , Stone Structure and Treatment. Proceedings of the International Symposium on Renal Stone Research . Edited by L. Cifuentes Delatte, A. Rapedo and A. Hodgkinson . !\lew York: S. Karger, p. 216, 1973. 18. Nordin, B. E. C.: Urinary tract calculi. In: Metabolic Bone and Stone Disease . Baltimore: The Williams & Wilkins Co., p. 233, 1973. 19. Elliot, J. S . and Ribeiro, M.: Calcium oxalate solubility in urine: the state of relative saturation. Invest. Urol., 5: 239, 1967. 20. Robertson , W. G., Peacock , M. and :-,.;ordin. B. E .: Activity products in stone-forming and non-stoneforming urine. Clin. Sci., 34: 579, 1968. 21. Smith, L . H. and Meyer, J.: Personal communication.
t