Paper - The origin and growth of renal calculi (1937)
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The Origin and Growth of Renal Calculi
Alexander Randall, M.D.
- Submitted for publication March 1, 1937, being the Annual Oration of the Philadelphia Academy of Surgery.
Five thousand years before the Christian era a man died in the upper Nile Valley, and his body was prepared for burial following the custom of his day. A few years ago an English archeologist, on examining this grave, found a concretion lying among the pelvic bones, which, on analysis, was found to be composed of an outer crust consisting of calcium-magnesium ammonium phosphate and an inner body consisting of almost pure uric acid crystals. Through the intervening seven thousand years, therefore, the chemical character of urinary calculus has remained unchanged. Likewise, the surgery of “calculus disease” enters medical history with its very beginning and, following many strange and interesting vicissitudes, comes down to us today broadly considered in all surgical writings, occupying through all time a prominent place in the surgical clinic, and hallowed by the names of all great surgeons of the past. As such it has come to be known as “calculus disease,” and surgery’s effort has remained little changed, interpreting its duty to be the removal of this morbid product.
It is to be part of my present effort to change this point of view, and to try to show that urinary calculus is but a symptom of a deeper underlying pathology. The problem is, without question, a complicated one. Were this not true, the etiologic factor, and perhaps a mode of cure and a method of prevention, would have been developed long ago, for much clinical investigation and serious research has been performed, as well as no small amount of logical theorization and some sheer speculation. Though we have amassed much valuable information, we still lack many important facts, and there still remain quite a number of pertinent questions unanswered.
On the one side appears the clinical state of a patient with symptoms easily recognized as arising from a renal calculus, as perhaps he is suffering his primary renal colic from nature’s effort to expel such a stone; surgery intervenes, and a crystalline concretion up to I cm. in diameter is removed. This stone is composed of crystallized salts normally present in the urine; it is not a foreign body; it is, and it has to be, the product of some morbid process.
Contraposed to this clinical state, and in an effort to explain it, stand today five pertinent theories as to why such a stone developed. Each theory is supported by interesting and acceptable research bearing on experimental stone production, with substantiating clinical studies suggesting a close relationship between the theory and fact. It is my purpose, first, to analyze briefly these five theories and to show the fallacies of each, or at least their shortcomings. It is only fair to state that in no research to date has the actual origin and the growth of a stone been traced from the first deposit of a tiny crystal of microscopic size, through the stages of added salt deposition, to macroscopic size when clinical symptoms may have supervened. We have accepted the theoretical inferences whole-heartedly, and with the simpleminded attitude so aptly expressed in the famous remark of Topsy, “I just growed.”
The Theory of Stasis
The theory is simple: That when faulty drainage causes stagnation of the urinary flow, sedimentation and crystallization of urinary salts can take place about any nidus. The picture is familiar in vesical calculus as a complication of prostatic obstruction with residual urine, and one transfers this picture to the renal pelvis, where somewhat similar conditions of urinary stasis, both congenital or acquired, do occur.
Clinically, the incidence of hydronephrosis with stone is well known; with pyonephrosis stone is more frequent; and one is asked to include those possible states of faulty renal drainage that theoretically accompany the necessity of being long bedridden.
Experimentally, such hydronephrotic conditions have been created with some success in the production of calculi, while the introduction of foreign material, as infection, regularly increases the incidence of such experimental stone formation.
Discussion — This theory—that stasis causes stone—though active in certain cases, fails utterly when such stasis can be proven to be absent. Also, it must not be overlooked that the finding of a stone in an hydronephrotic pelvis does not prove that the stasis caused the calculus; for often the reverse is true—that the stone came first and caused the hydronephrotic condition. Since the introduction of intravenous urography it appears that by far the larger percentage of renal calculi, especially when seen early, can be clearly proven to occur in kidneys totally devoid of stasis or faulty drainage, and in patients actively employed at normal occupations. Again, neither is it a constant fact, nor clinically is it expected, that every kidney pelvis which is poorly drained, even if infected, will sooner or later form stone; and the picture again is comparable to the occurrence of vesical calculus in prostatic disease, where, according to the highest figures published, calculus occurred in but 20 per cent. As germane to the subject at hand, let it be stated here that the material to be presented later especially excludes stasis as a factor in the etiology of stone, and in the clinical cases that will be shown only those proven to be free of stasis will be considered.
The Theory oF Infection
In this theory both clinical studiés and experimental work come closer to a solution of the problem.
Clinically, we have the rather prevalent finding of infection in operative cases (which unfortunately are seen late in the disease), until an unproven axiomatic statement has gained rather general credence, “that if every case of renal calculus be traced to its ultimate end, an infection would be found underlying it.” Some highly suggestive observations have beeni made: The prevalence of calculi as a complication in chronic infections of bone; children with Pott’s disease; long-standing osteomyelitis cases; the observations during the late war in severe bone injuries with long drainage; and similar cases in industrial surgery ; all pointing to a close relationship between chronic infectious processes, especially if such have periods of exacerbation, and the occurrence of renal calculi. Of real importance is the clinical observation of the role that infection plays in the recurrence of renal calculi and the incrustation of urinary fistulae, especially with that group of organisms capable of breaking down urea into ammonia, causing a persistent alkaline urine and the rapid precipitation of urinary phosphates.
Experimentally, it is quite essential to our clear understanding of the relationship between infection and the etiology of stone to realize at the very beginning that it is almost impossible to implant an infection in the undamaged and unobstructed urinary apparatus. Even in those cases found with stone and infection present, it is faulty reasoning to assume that the infection preceded the stone. It is a uniform observation, in both clinical and experimental work, that infection always increases the incidence of stone occurrence (or recurrence) and augments the rapidity of growth of calculi. The experimental work under this theory culminates in the report of Rosenow and Meisser, where they infected the devitalized teeth of dogs and inoculated the pulp cavity with cultures of “specific” Streptococci obtained from urinary calculi, and obtained 60 per cent positive results. This work has been neither corroborated nor challenged and disproved. It stands as probably the nearest approach to the clinical picture by the purely experimental production of renal stone; though it is to be stated clearly that these authors do not actually show us how, or where, or why, a calculus develops.
Discussion — The theory of infection accepts such metastatic organisms as producing a pyelitic infection, and assumes that. such bacteria, or their morbid products, create the nidus about which crystallization forms a stone. It does not admit that sterile cases of stone occur—which clinical studies unquestionably confirm—nor does it agree with the modern belief that organisms do not, and cannot, pass through the kidney without producing lesions. It is regrettable, on the other hand, that clinical cases too often are seen so late that secondary infection cannot be ruled out; but to anyone who cares to focus his attention only on the early cases—the small calculi, the primary attacks—it becomes increasingly evident that infection per se is not a part of the picture of either the clinical state of the patient, nor the laboratory studies of cultures of the affected renal pelvis. Moreover, the experimental workers have not traced the complete story from infection to actual stone formation, and have taken too much for granted between theory and fact. As will. be presented later, our investigations contravert the role of local infection entirely.
The Theory oF Vitamin Deficiency
This theory is beginning to crystallize, under its heading, the entire role of diet in stone formation.
Clinically, it attracts attention from two distinct angles: First, and perhaps of the greatest importance, is the realization that stone of the bladder in childhood has almost disappeared from the picture of surgery. This change has occurred within the memory of living man, and without the medical profession taking any active part in advocating steps for its deliverance from this true scourge. The figures show that one hundred years ago in Europe and American over one-half of the operations for vesical stone were performed upon children. Today these operations are a rarity, and undoubtedly the liberalization of the dietary of infancy and childhood is the sole responsible factor. Second, is the realization that it is vitamin A, and to a lesser extent vitamin D deficiency, that is responsible, causing a disturbance of the calcium phosphate ratio. The clinical importance of this knowledge is rapidly growing, especially in the field of postoperative prevention of stone recurrence.
Experimentally, much could be told, since 1917, when Osborn and Mendel reported their observations in rats following certain diets. Actually, no tissue suffers more severely from want of vitamin A than the epithelium lining the urinary tract (McCarrison). Epithelial degeneration, desquamation and keratinization are characteristic of the condition. In experimental animals calculi do appear in the renal pelvis, and more frequently in the bladder, the frequency of which is in direct ratio to the length of time avitaminosis is continued. Other related factors are the consistent elevation of the pa value in the urine to marked alkalinity, and the fact that the incidence of urinary infection is practically equal to that of stone formation.
Discussion of this theory must be confined to those factors known to be truly relevant. First, it is to be pointed out that the calculi that form under conditions of avitaminosis are consistently made of those salts known to have their normal ratios disturbed ; that is, calcium-phosphate. Stones of uric acid, urates, or even calcium oxalate, do not participate in the picture at all. If the phosphorus is radically diminished in the diet, calcium carbonate can be made to crystallize, and occasionally calcium and magnesium phosphate have been observed. Second, is to be noted the alkaline urine and the high incidence of urinary infection in the experimental rats; factors not unusual in clinical urologic surgery, and in keeping with our knowledge of the ready precipitation of phosphatic incrustations under such conditions. Third, it appears that the earliest formation of crystalline material is about desquamated epithelial cells acting as a nidus, and vesical stone is much more frequent than renal stone, though neither appears until marked epithelial changes have developed. It is of interest to point out the possibility that large numbers of an apparently otherwise healthy population may be living under varying degrees of avitaminosis. The perfection of the Jean’s test for deficiency in visual purple, as a delicate means of estimating slight degrees of vitamin A deficiency, is a most promising clinical aid; though at present this theory must limit itself to the calcium phosphate stone as met clinically.
The Theory oF CoLLomaAL Chemistry
This fascinating supposition lacks only the two essentials of tangible fact and unquestioned truth. It assumes the recognized action of colloids to hold in solution the crystalloids of the urine and, not only to hold them in solution, but in a supersaturated state.
It is one of the many ingenious provisions of nature whereby it rids itself, even under physiologic conditions, of considerable amounts of excreted solid substances in the least possible quantity of fluid. The normal daily amount of colloid is sufficient for the elimination of the normal daily amount of crystalloid; but it is a delicate balance and is, therefore, assumed to be quite unstable, with a constant tendency to gain a more stable condition by having the crystalloids fall out of suspension. If one disturbs this so called colloidal balance by either increasing the crystalloid, or decreasing the colloid surface area, there occurs a precipitation of the crystalloids and their appearance in the urine as actual insoluble material. Such may be called the clinician’s simple viewpoint of the intricacies of colloidal chemistry, in which one can hardly expect the physiologic chemist to wholly concur.
Clinically, it is pointed out that infection and epithelial degeneration are recognized disturbers of the colloid mass, either actually depreciating the amount, or causing coalescence with loss of surface area. Again into this theory will come all cases of hyperexcretory nature, where there is eliminated actually more crystalloid than there is colloid to hold it in solution.
Experimentally, this has been tested successfully by feeding animals excessive amounts of crystalline material, and so producing a condition of hyperexcretion. With the feeding of oxamid in large quantities, actual calcium oxalate stones have been produced, and recently Keyser (1936) has accomplished the same end by pushing calcium carbonate to the point of hyperexcretion. The remaining experimental work on the role of colloidal chemistry becomes so involved in theory, and so remote from clinical fact, that it bears little relation to the clinical problem at hand; though mention should be made of the suggested réle of colloid material as the primary gel on which crystallization starts, and the colloid matrix to be found in the lamina of all calculi.
Discussion of this theory may be brief, for there is too little known of the intimate action of colloidal chemistry in both renal secretion and urinary excretion. Certain it is that fallacies creep in, for we all see patients with chronic phosphaturia, oxaluria and, best of all, cystinuria, who for years live with some such perverted metabolic balance and yet, even in this hyperexcretory state, fail to form stone. Moreover, this theory, though interesting in many ways, does not open any plausible lines of thought which may be subjected to experimental proof as actually causing a stone to originate. But there is to be said at this point that our knowledge regarding the colloidal balance of the urine, and the supersaturated condition in which urine is excreted, probably does play an important part in the determination of the type of salt to be deposited, once the causal factor is recogriized.
The Theory of Parathyroid Hyperfunction. — This latest addition to the theories bearing on the etiology of renal stone is probably the most positive of all.
Clinically, we now know how to recognize hyperparathyroidism, and in its recognition we have an explanation relative to the disturbance in calcium metabolism and the characteristic bony changes in generalized osteitis fibrosa cystica. The metabolic disturbance is accompanied by a high tide of calcium in the blood and an increase of calcium in the urine. At the same time there is an increased urinary excretion of phosphorus in spite of a recognized decrease of serum phosphorus. Here we have, from a spontaneous clinical state, a typical reproduction of a hyperexcretory state under which stone has been made to form in experimental animals. This is not to be passed over lightly, for renal calculus has been recognized in 65.7 per cent of the 35 cases of hyperparathyroidism studied at the Massachusetts General Hospital.
Experimentally, the investigative work is being rapidly pushed, for the production and utilization of parathormone have given us a valuable aid in reproducing this pathologic state. There are no details to report as yet.
Discussion. — Valuable as this observation is, and as closely related to renal stone as it appears to be, there is lacking at present a definite relationship between parathyroid dysfunction and all urinary concretions. The disturbance is only in the calcium-phosphorus balance, and one wonders how it could play a part in oxalate, urate or uric acid calculi. In fact, the answer is again to be found in the studies at the Massachusetts General Hospital, for in a series of 300 cases of renal calculus they could prove hyperparathyroidism present in but 5 per cent.
That no one of these five theories fulfills the demands of clinical medicine and the recognized vagaries of the chemical composition of stone is the reason that each remains but a theoretical picture of the problem. Later there will be pointed out a possible relationship wherein the theory of parathyroid hyperfunction, as well as the theories on avitaminosis and that on colloidal imbalance, and perhaps that of infection, can be definitely interrelated, and perhaps found individually responsible, at times, for the causation of stone growth in the kidney. When one considers these five theories, sees their divergent angles, realizes their indisputable deficiencies and, at the same time, recognizes the varying chemistry of the stones themselves (where seven or more salts are involved and frequently present in pure or in mixed states), one feels that Howard Kelly was quite within the bounds of reason when he wrote: “No stretch of chemical or physiologic imagination will permit so heterogeneous a group of compounds to be ascribed to a common origin, or their deposition, in kidney, ureter or bladder to be uniformly charged to an identical cause.”
It is the purpose of this study to trace the trail that has been followed during the past seven years, working through theory to certain facts that, of themselves, created an hypothesis. From this hypothesis two postulates were drawn and the work of proof inaugurated. There has been an effort to work back to what might be called a study of calculo-genesis; the stone’s conception ; its embryonic growth; its fetal life cycle; up to the point where size and symptoms made it a clinical entity and clothed it with raiment familiar to surgeons.
With this background of the common knowledge on the etiology of renal calculus, we wish to point out, very briefly, the various experimental research problems that have absorbed our interest and endeavor, omitting many details for the sake of brevity, but outlining the train of reasoning that has been followed.
(1) An analysis of calculi was made to determine the chemical characteristics, thinking that perhaps the problem had to be broken down into its component parts in order to determine the individual origins. It was assumed that perhaps the cause for the growth of an uric acid calculus was entirely different from that of a calcium oxalate stone, and that perhaps a different chapter would have to be written for each variety of chemical composition, with a differing etiology for each. This problem has not been productive of results. Three hundred and ten calculi have been analyzed* and compared to the history and clinical studies without finding any specific lead between cause and effect. In this series calculi composed of uric acid, sodium urate, ammonium urate, calcium phosphate, calcium oxalate, calcium carbonate, calcium-magnesium phosphate, calcium-magnesium and ammonium phosphate, and cystine have been encountered. These studies in part have been published.
(2) We tried to infect the renal pelves of dogs by implanting organisms by cystoscope and ureteral catheter. Several exogenous and endogenous organisms were used, and when results were not forthcoming, organisms cultured from stone cases, both renal pelvis cultures and cultures from the center of calculi, were tried, but again without success.
(3) Realizing the improbability of being able to implant a culture in the healthy renal pelvis of the dog, we repeated some of these attempts, and endeavored to traumatize the renal pelvis by a wire projecting from the end of the ureteral catheter. Again success was so uncertain that the problem was abandoned.
(4) The foregoing failures taught us that a lesion was necessary to effect the implantation of an infecting agent. Twelve dogs and eight rabbits were employed. In some a pyelotomy was performed and different kinds of trauma to the pelvic walls effected by instrument, fulgurating electrode, or chemical burn. These pelves were then infected with organisms from a man who had had seven operations for recurrent urinary calculi. In others of these animals one or both ureters were opened in the middle third, and the traumatizing instrument passed to the pelvis under hand guidance, in order to keep the operative field at a distance. In this series we effected six lesions—five
Of the kidney calculi, numbering 151 cases, 71 of the stones, or 47 per cent, occurred as pure salts, as follows: Calcium-magnesium phosphate, 39; calcium oxalate, 11; triple phosphate, 7; uric acid, 6; calcium carbonate, 4; cystine, 4. Of the ureteral calculi, numbering 159 cases, 100 of the stones, or 62.9 per cent, occurred as pure salts, as follows: Calcium-magnesium phosphate, 49; calcium oxalate, 39; uric acid, 7; calcium carbonate, 4; cystine, 1. The remaining 139 cases had stone or stones of mixed salts in 28 differing combinations. I am deeply indebted to Drs. H. G. Beeson, C. A. W. Uhle and P. D. Melvin for this painstaking routine study.
successful implantations of infecting organisms—and in two dogs we were able to produce visible sand or gravel. In the eight rabbits we produced six lesions, of which three held the infection, two healed, and one unhealed was sterile at autopsy. Triple phosphate sand was found in one.
(5) A group of rats were put on vitamin A deficiency diets, and a search for characteristic lesions was made. These rats were part of an extensive vitamin A problem. In some we obtained evidences of early aseptic ulcerations, but the vitamin deprivation was marked, and death occurred too early for the characteristic calcium phosphate deposits to be formed. This series is now being repeated with 96 rats at the Wistar Institute as part of a further study of the problem.
(6) During this period of experimentation clinical cases were watched, searched and studied to correlate chronic focal infections with the occurrence of renal stone, and it may be noted in passing that these studies do constantly bear evidence of such close relationship, and deductions therefrom have been published. But in this research we were unable to obtain other than the suggestive finding between theory and fact exemplified in the experimental problems or the clinical studies.
Such were some of the lines of endeavor that were pursued in the hope of finding leads which would be promising to follow in order to experimentally produce stone and allow of clinical interpretation or further study of the early changes that are creative of calculus growth. It is perhaps now evident that our entire line of thought was predicated upon the firm belief that renal stone is but a symptom, developing upon some underlying and preexisting renal pathology ; and most of our efforts were bent toward making an infection the basic and fundamental primary cause.
If one divorces oneself from the plethora of theory in this field, and looks at the problem from a more detached point of view, certain questions arise that are extremely helpful to a clearer insight into the problem as a whole.
One cannot dwell upon the origin of primary renal calculus without, sooner or later, forming a firm conviction that there has to be an initiating lesion. Everything points toward it, every known fact strongly suggests it, every pertinent question demands it, and pathology itself is incomplete without it! Stone is a symptom, and not a disease entity. Stone is made from the common salts in the urine. These salts exist in a supersaturated state. Stone will grow on any foreign tissue or foreign body. Stone has got to be a gradual accretion of crystals demanding a nidus for the seeding of such crystallization. Stone requires time to grow and, therefore, must be stationary and fixed in its beginning in order to gain clinical size. Therefore, as our researches progressed, though they were unproductive of positive results, they at least seemed to help to crystallize in our minds the idea that all renal calculi must have, as a point of origin, some preexisting lesion in the renal pelvis. It was the growth of this idea—the absolute necessity of such an initiating lesion—that led us on and that suggested the above experiments with trauma and infection.
Gradually in the course of our researches there was evolved a hypothesis which, as stated, predicated the origin of any stone upon the existence of a previous lesion, and we made as our first postulate: That there must be an initiating lesion that precedes the formation of a renal calculus. It was perfectly evident that in none of the researches on renal calculus had any one observed the actual origin, development and growth of a stone. Nowhere could be found the stages between theory and fact. Even those who had succeeded in producing calculi experimentally had not attempted to trace the actual onset and developmental stages, and practically all left one with the impression that a stone floated about in the renal pelvis while it grew in size, or else some perversion of nature nurtured this aggregation of crystals until it was at least large enough to produce a renal colic. The story of what might be called “calculo-genesis” had not yet been written.
If our first postulate demanded an initiating lesion, it naturally became evident that a second postulate would be necessary as to where such a lesion might be expected to be found. It was not difficult to exclude the probability that the simple lining epithelium of the pelvis and calices would produce the initiating lesion; their resistance is high and their anatomy and physiology are simple. The renal papilla on the other hand is quite the reverse; performing a complicated function, open to multiple physiologic variations, and known to suffer recognized insults that lead to pathologic changes. Therefore, a second postulate was formulated: That the initiating lesion was to be looked for on the renal papilla.
A search of the literature for what is known of the pathology of the renal papilla was most disappointing. The hemorrhagic papillitis of Fenwick, the uric acid infarcts of the newborn, the calcium infarcts of Henle, and the occurrence of tuberculous ulcerations (Lieberthal) cover about all that have been recognized as primary lesions. As our experimental efforts had been abortive of results, it was decided to go to the autopsy table and, by dissecting out each minor calyx to the complete exposure of its individual papilla, to uncover whatever observations awaited us, and to hope that time, patience and industry would reward our efforts by possibly showing us lesions that could be related to stone’s origin and growth and, perhaps, to the finding of early crystalline deposits. In other words, instead of trying to create stone by following theoretic dogma, we turned to trying to find stone as it occurred in man, and to observe it in its incipiency, its point of origin and its causal factors. The cooperation of the Department of Pathology at both the Hospital of the University of Pennsylvania and the Abington Memorial Hospital made this effort possible and, at my request, each put at my disposal the kidneys from all autopsies, to be opened and _ sectioned as we saw fit. These kidneys were examined by first opening the pelvis, and from it, by careful dissection, each major and minor calyx was laid open in turn and each papilla completely visualized and studied with a hand lens. During the past six months the autopsy material from the Philadelphia General Hospital has been added, though here the kidneys have been routinely examined before we receive them.
Starting in December, 1935, there have been examined to date (February 15, 1937) 429 pairs of kidneys. Of this total number 73, or 17 per cent, have shown papillary lesions, either unilateral or bilateral, of one or more of the renal papillae. As above stated, our interest has centered particularly about what might be called the minor pathologic changes, and kidneys showing gross destructive pathology—pyonephrosis, advanced tuberculosis, etc.— are not included at all. In other words, kidneys heretofore passed as having normal pelves have been the ones we particularly searched for early papillary lesions.
Let me digress a moment to draw attention to two clinical observations that have been repeatedly noted by us, and which should be mentioned at this point as bearing upon this research and to a degree suggesting it. First, the small calculi, which we have studied over a number of years, consistently showed a certain peculiarity; especially those whose clinical history was of short duration, evidencing that there had been but a brief interval from the time of becoming clinically obstructive to the moment when they were removed from the urinary tract. Hand lens examination of such calculi regularly showed a surface highly crystalline, but also a portion which was smooth and somewhat depressed, resembling a facet. This facet was so consistent in its occurrence in these clinical cases that it was early taken as suggestive evidence that the calculus had had a mural attachment. Such small calculi have been photographed and enlarged, have been sectioned and polished, and the observation has been repeated so many times that it stands as quite positive circumstantial evidence of the mural origin and attachment of stone while attaining what might be called clinical size. Secondly, this suggestive observation has made us study our roentgenograms more closely for the localization of small stone shadows, and since the introduction of intravenous urography, we have been pleased to find that such early calculus shadows can be proven to occur most regularly in the minor calices.
Starting our postmortem series we examined 27 normals before encountering our first papillary lesion. This lesion was so innocent in appearance, and yet so definitely abnormal to our previous observations, that it demanded attention. There was present a cream-colored area near the tip of the papilla, which was definitely not on the surface, but appeared to be sub-epithelial. Shortly thereafter we found four kidneys that showed a similar lesion— some with a solitary plaque on only one papilla, others with several papillae involved, some unilateral in occurrence, others showing bilateral papillary involvement. On microscopic study, the lesion was found to be a plaque of calcium deposited in the interstitial tissue of the renal papilla, and definitely not intratubular. Special stains were used to identify this as calcium, and material has been collected by teasing out such plaques, which on being analyzed chemically was proven to be calcium.*
It is my wish at this point to especially emphasize that this lesion, as we have found it, occurs particularly in the walls of the renal papilla—some centrally placed, some just subsurface—that it is not an intratubular deposit, but a broad plaque of calcium invading and replacing interstitial tissue (Figs. 1 and 2); that, from our studies, its first deposition is in the collagenous, or basement membrane of the terminal tubule walls, from which it gradually involves the intertubular spaces and causes the tubules to gradually shrink, lose their lining cells and disappear, or remain with markedly narrowed lumens; that in the many sections which we now have studied, of practically all the lesions above mentioned, in only two has there appeared cellular destruction and round cell infiltration, which could be interpreted as evidence that infection accompanied this calcium deposition. These exceptions I consider as the inevitable finding when taking such material from the autopsy table, and consider that it represents a secondary factor where infection has been implanted upon a preexisting pathologic condition.
It was not long before a kidney was found where, on such a calcium plaque, a secondary deposit of some black material could be seen. This deposit was about the size of the dot over the printed letter “i,” and quite as distinctly visible (Figs. 3 and 4). Sections of this specimen showed evidence that, through increasing growth and pressure, this calcium plague had lost its epithelial covering, and on its surface was deposited a layer of some different material. Its minute size defied analysis and specific staining methods; but from our subsequent studies we now look back upon this tiny speck as the earliest evidence of renal calculus formation ever seen.
Our next important step arrived with the examination of a kidney in which a small stone was found, which was, however, unfortunately dislodged by the knife as the kidney was opened; search, however, revealed another papilla which contained a visible calcium plague, upon and from which a second stone projected into the lumen of the minor calyx (Figs. 5 and 6). This stone was firmly adherent, measured approximately 2 Mm. in diameter,
Dr. James H. Jones of the Department of Physiologic Chemistry of the University of Pennsylvania analyzed 4.65 mg. of such material for me, to find calcium to occur in 4.967 per cent (5 per cent). As muscle, liver, lung and kidney contain only 0.1 to 0.5 per cent, it left but little doubt that calcium was present in high concentration. Dr. Charles G. Grosscup of the Abington Memorial Hospital, with 1.9 mg. of material, similarly composed of plaques teased from visible papillary lesions, undertook a quantitative analysis. He reports that the material was microcrystalline and chalky in appearance, was insoluble in water and acids, but dissolved in alkalies. Quantitatively calcium was present in 19 per cent, nitrogen in 10 per cent, CO: in 1 per cent, and phosphorous present but difficult to make accurate quantitative estimation. He states, “In view of the low CO: and phosphorus content and high calcium (19 per cent), it was evident that about 80 per cent of the calcium must be bound in some other form. With the murexide test indicating xanthine, the insolubility of the material in acids and the high nonprotein nitrogen suggest that this may be nucleic acid.”
and resembled in appearance the larger calculus which the knife had dislodged. Study of these specimens has been most valuable: in the first place the dislodged stone has been analyzed and proven to be composed of calcium phosphate; microscopic sections of the smaller, adherent stone have demonstrated unquestionably that it is growing from, and is supported by, a typical calcium plaque imbedded in the wall of the renal papilla; special stains have shown that the stone is of calcium phosphate, while the plaque itself is composed of calcium but does not show phosphate as a salt. So here we have a definite renal calculus growing on an initiating lesion, and the lesion is a deposition of calcium in the walls of the renal papilla, and the two are of different chemical composition. The demonstration of this fact becomes a most vital factor in our conception of the origin of renal calculus, and should be emphasized. Here, for the first time, we find a lesion of not infrequent occurrence (17 per cent), and of rather constant character and chemical composition. This lesion, innocent enough while buried in the wall of a renal papilla, can lose its epithelial covering and from then on be bathed in calyceal urine, and acting as a foreign body, it becomes the nidus upon which urinary salts precipitate. Here, likewise, we can picture the reason how and why renal calculi can remain stationary while increasing in size. Here we can account for a common origin of stone formation, which also allows of the known variation of salts so deposited to form stone, and one can assume that the salt which does crystallize to form a calculus is the one which, at that epoch, is most readily thrown out of suspension. Study of the serial sections through this stone has likewise shown us, at the edge of the plaque, a definite elevation of the plaque by the encroachment of crystallization, which suggests that when a stone becomes free, it does so by tearing the plaque from its tissue bed and taking it away with it.
From this point on our studies have taken a variety of directions. We have observed to date 14 kidney specimens, in which calculi have been seen growing upon papillae. Eight of these have had a single stone present, in five of them two papillae were found with stones adherent, and in one case all six papillae supported stone deposits. This makes a total of 24 observations where calculi have been found actually adherent to, and growing upon, a renal papilla. To these may be added four other specimens where the calculus was less than 1 Mm. in diameter, but which were as plainly visible as a cinder on the cornea of the eye. Each of these has been sectioned and this earliest deposit proven microscopically.
Fig. 1. — Drawing of a typical subsurface calcium plaque in the wall of a renal papilla.
Fig. 2. — Detailed drawing of high magnification of a subsurface calcium deposit on the renal papilla. Note the shrunken tubules at the base of the plaque, their loss of normal epithelium, and the absence of any reaction suggesting infection.
Fig. 3. — Colored photograph of a renal papilla, showing the subsurface calcium deposit, and in its center a tiny black secondary deposit. This the earliest evidence of secondary deposit which forms stone.
Fig. 4.—Colored photomicrograph of Fig. 3, showing the calcium plaque which has lost its covering mucosa, and on which is a secondary deposit of brown material, taken to be the earliest evidence of renal calculus formation. No evidence of infection.
Fig. 5. — Colored photograph showing calcium deposits in two papillae, and a stone attached and growing on the calcium deposit in the third papilla. Another stone of similar character found in this kidney has been analyzed and proven to be composed of calcium phosphate.
Fig. 6. — Colored photomicrograph of Fig. 5, showing the papillary stone attached to its calcium plaque. The differential staining shows the stone composed of calcium phosphate. The plaque with some phosphate staining; counterstains for calcium of different composition. No evidence of infection.
It has been our purpose to try to demonstrate that each of these calculi was supported by a primary intrapapillary calcium plaque as its initiating lesion. That this is exceedingly difficult will be readily understood. In the first place such calculi have to be properly decalcified before sectioning—not completely decalcified, of course, but enough to allow sectioning—and in doing this we have lost specimens. Again, we have tried to depend upon special stains in an effort to differentiate the various possible salts, which has required special methods of tissue fixation. This, in turn, has dissolved some specimens, and others have been made so brittle as to be completely fragmented on sectioning; and this has resulted in the loss of some specimens. In addition, it has been difficult, and most tedious, to attempt complete serial sectioning of stones 6 and 8 Mm. in diameter, in order to cut through the stone and its possible underlying plaque, which frequently is minute and generally eccentrically placed. In order to avoid these disappointments, two other procedures have been adopted in order to prove that each calculus arises from a calcium plaque in the wall of a papilla. First, a few selected specimens have been subjected to tissue-clearing methods, and by this means we hoped to visualize through the cleared papillary wall the underpinning of the calculus upon the papilla’s surface. The second method was discovered accidentally, when a tiny black stone, 3 Mm. in diameter, was inadvertently dislodged ; on examining it under a strong lens, it was seen to be distinctly composed of a black mass with a bossed surface, simulating the early jackstone development of the calcium oxalate stone, but to one surface a clear-cut white layer was adherent, distinctly different and definitely crystalline: this we inferred to be the calcium plaque. Through the cooperation of Dr. A. Newton Richards these two layers were analyzed separately. The calculus weighed 5.5 mg. (Fig. 7). Microchemical analysis was made, which showed that the white layer, or plaque, was composed of calcium carbonate, with a decided trace of calcium phosphate. The black stone gave a negative test for calcium carbonate, calcium phosphate and uric acid, but was conclusively proven to be pure calcium oxalate. This is a most significant finding, for here again, on a papillary plaque composed of calcium carbonate and calcium phosphate, a stone composed of a different salt has formed (calcium oxalate). Two other calculi of similar character have been gently dislodged from their papillary attachments, and in each case the white plaque is plainly visible. This, to a degree, supports the assumption that as a calculus is extruded in life, it gains its freedom by tearing away its supporting plaque from its original tissue bed.
While these researches have been furthered in an effort to substantiate the idea of a papillary initiating lesion, and to quite definitely prove the réle played by the finding of the calcium plaque formation and its relationship to the clinical occurrence and growth of a renal calculus, we have been keenly interested also in trying to solve the raison d’étre of the deposition of cal 1021 ALEXANDER RANDALL Annals of Surgery
cium in the papillary wall. This work is far from finished, but it is possible, at the present time, to give the pathology as we have interpreted it. I am obliged especially to Dr. John Eiman, Pathologist to the Abington Memorial Hospital, for the following detailed description and to Dr. Balduin Lucke, Professor of Pathology, University of Pennsylvania, for his interest and aid in obtaining special staining methods and in section cutting, as well as his coincidence with the opinions expressed on the microscopic pathology.
Microscopic Pathology. — Normal Papilla: The normal papilla is covered by cells which differ from those lining the calices and the collecting tubules, in that they are a single layer of flat, very thin cells which are modified cells of the lining epithelium of the collecting tubule. The collecting tubules in the papilla vary considerably in diameter, the larger ones, or the ducts of Bellini in the area cribosa on the apex of the papilla, measuring from 100 to 200 microns in diameter. The cells lining the collecting tubules are arranged as a regular single layer, with their nuclei at one level and their free surfaces bulging slightly into the lumina. The smaller collecting tubules are lined by sharply defined cuboidal cells. As the collecting tubules grow larger, the cells become higher and in the ducts of Bellini acquire a tall columnar form. The epithelium of the collecting tubules rests upon a well developed and distinct basement membrane. The interstitial connective tissue in the papilla is more abundant than in the cortex and medulla of the kidney, and there is an abundant amorphous ground substance.
The Calcium Plaque: Figs. 1 and 2 (Specimen No. 36-7, U. of P.). Approximately midway between the tip and the base of the papilla, underneath the epithelial covering, is an area, measuring 2.5 Mm. in length and varying from 0.1-0.3 Mm. in width, composed of dense connective tissue. The surface of the papilla over this area is somewhat irregular. The blood vessels in this location are less numerous, and those present are partially obliterated by the surrounding dense connective tissue. Some of the collecting tubules are devoid of lining epithelium, while other tubules show cells evidencing degenerative changes. In the portion of this region nearest the tip there are a number of small areas showing granular detritus. In this location are seen two small irregular deposits of purplish-staining material ( H. and E.) measuring approximately 0.3 by 0.03 Mm. By special staining methods* these deposits proved to be calcium. These calcium deposits, or plaques, are separated from the surface of the papilla by a thin irregular layer of connective tissue and covering epithelium. Where the calcium is less dense it occurs in rings, definitely deposited in the basement membrane and spreading into the ground substance of the surrounding connective tissue.
Throughout the papilla, but especially near the tip, there are areas showing an increase of interstitial connective tissue. Some of the blood vessels show narrowing and irregularity of their lumina. The cortex and medulla show no noteworthy lesions. The walls of the convoluted tubules show no calcium deposits. - The larger vessels show a moderate degree of arteriosclerosis. There is no microscopic evidence of infection in this specimen.
(Specimen No. 36-42, U. of P.): Near the tip of the papilla is a calcium deposit measuring approximately 0.3 by 0.3 Mm. It is separated from the surface by a layer of connective tissue and covering epithelium varying in thickness from a few strands to .06 Mm. The surface of the papilla shows a practically normal covering except at one point near the plaque where there is a depression about .o5 Mm. deep. Most of the collecting tubules near the plaque are devoid of their epithelial lining, but an occasional tubule shows small clumps of partly degenerated and desquamated epithelial cells. Blood vessels near the calcium plaque are diminished in number ; they are distorted and show various degrees of compression to the point of obliteration. Around the dense calcium plaque are seen ring-like deposits of calcium in the basement membrane of the tubules. There is no microscopic evidence of infection in this specimen.
The special stains used in this study are: von Kossa, Eros, Giemsa, Masson, azocarmine, elastic tissue stain, Grandis and Mainini, methylene blue, and picric acid stain for urates and uric acid.
Fully Developed Initiating Lesion: Figs. 3 and 4 (Specimen No. 36-43, U. of P.). Near the tip of the papilla there is a loss of continuity of the surface with the formation of a shallow depression. In this depression is situated an irregular plaque, measuring 0.6 Mm. in length and from 0.1-0.2 Mm. in width, which by special stains was proven to be calcium. The plaque shows numerous small, roughly rounded spaces which vary in size. Over the surface there is an irregular layer of brownish material which measures 0.025 Mm. in thickness; this layer is definitely of different material than the calcium plaque. The calcium plaque is not uniform in texture; in the looser parts about the periphery the calcium is seen deposited in the basement membrane of partly compressed collecting tubules. There are a few tubules which show deposition of calcium in some of the lining cells, while other cells are completely preserved.
Special stains show that when the calcium is to be deposited, it appears to be laid down first of all as fine granules in the basement membranes of the collecting tubules. With further deposition such granules coalesce until the calcium appears as a complete ring encircling the tubule, generally with loss of epithelial lining, though occasionally there can be found some viable cells. From this point, calcium is further deposited in the ground substance of the surrounding connective tissue, with gradual generalized coalescence and plaque formation. There is no evidence of a deposition of calcium in the epithelium of the convoluted tubules.
Near the plaque and at the tip of the papilla are seen many large, roughly rounded, irregular spaces, many of them devoid of epithelial lining, but some showing epithelial cells in different stages of degeneration. These large spaces undoubtedly are cross sections of large collecting tubules or ducts of Bellini that have lost their normal epithelial lining. Toward the base of the papilla the dilatation of the collecting tubules is less marked, and the lining shows consistently larger numbers of epithelial cells of lesser degrees of damage. There is no microscopic evidence of infection in the specimen.
This we have termed the fully developed initiating lesion, for here we see, for the first time, a secondary deposit of entirely different staining properties laid down in laminae upon a simple calcium plaque: The essential point being that this plaque has lost its connective tissue and epithelial covering.
Calculus on Plaque: Figs. 5 and 6 (Abington No. 1). Near the tip of the papilla, 0.3 Mm. beneath the surface, there are irregular calcium deposits over an area 2.2 by 0.6 Mm. Near these deposits, on the surface of the papilla, there is an irregular calcium plaque measuring approximately 0.4 by 0.1 Mm. To the outer surface of this calcium plaque, and only to the plaque, is attached an irregularly shaped calculus measuring 1.75 by 0.8 Mm. This stone, by special staining methods, was proven to be composed of calcium phosphate, while the plaque on which it grows stains for calcium but not for calcium phosphate.
Here is microscopic evidence of a calculus of one chemical composition growing from the surface of an intrapapillary plaque of a different chemical composition.
All Lesions on One Papilla. (Specimen No. 32-682, U. of P.). This papilla shows a number of subsurface lesions. Near the surface on the side of the papilla there is a small roughly oval area, homogeneous in appearance, composed of dense connective tissue and showing very few partly degenerated nuclei. Close by, in a similar subsurface location, is a small necrotic area separated from the surface by connective tissue and covering epithelium. A short distance from this necrotic area toward the tip of the papilla is another area of necrosis showing deposition of calcium, yet still separated from the surface of the papilla by three or four strands of connective tissue cells. Still further toward the tip of the papilla is seen a small depressed area devoid of normal covering, with irregular fragments of calcium deposit at its base. Apparently something has been torn away from this area, carrying with it part of the calcium plaque. In no place is there any evidence of infection, or of calcium deposits in the convoluted tubules.
This section pictures a most fortunate find, for from this papilla we removed a black stone and on it have demonstrated its attached plaque (Fig. 8). Also, as described above, are demonstrable in this section: (a) An undisturbed subsurface calcium plaque; (b) an area of necrosis as yet without calcium deposition ; and (c) the earliest changes of simple fibrosis with some pyknotic nuclei (Fig. 9).
Discussion. — The general impressions obtained by a close study of these specimens are: That there occurs a definite damage to the epithelial lining
Fig. 7. — Calculus found attached to a renal Fig. 8. — Tiny renal calculus removed from papilla, which was manually removed. The a renal papilla (Spec. 32-682). The calculus specimen weighed 5.5 mg. and measured 3 Mm. weighed approximately 1% mg. and measured across. The black stone has been proven to be 1 Mm. This greatly enlarged photograph composed of calcium oxalate: the white portion shows the black calculus and its firm attachis the torn-out plaque from which the stone ment to the white calcium plaque, which was developed, and is composed of calcium carbonate torn out of its tissue bed on removal of stone.
of the collecting tubules, and that the nearer one goes toward the tip of the papilla the more noticeable the changes are; that there is a marked damage to the ground substance of the interstitial connective tissue and of the basement membrane of many of the collecting tubules. Here and there the ground substance is broken up and granular, and has a necrotic appearance. These changes appear to be followed by the deposition of calcium and calcium plaque formation. This study also reveals that in places the calcium is deposited in damaged epithelium of the collecting tubules, but the primary deposit appears to be in the basement membranes leading to the formation of ring-like structures. No evidence of infection is seen in any of the sections presented.
Mention should be made of five specimens in which this simple pathologic process shows additional features. In two of these five specimens the presence of bacteria has been demonstrated. Whether these are secondary in
Fig. 9. — All lesions on one papilla. On the left is a photomicrograph (low power) showing at A an area from which the calculus shown in Fig. 8
was removed. At B is a subsurface calcium deposit; while at C is an area of ischemia and necrosis. higher magnification.
Succeeding pictures are these three areas under vaders, or play a more important role in the papillary pathology, we are not prepared to state at present. It is certain, however, that the tissue changes and the pathologic processes seem to be fundamentally the same, and the entire picture impresses one as a more rapidly progressing lesion, a more generalized involvement of the papilla, and it is to be noted that each of these patients died from a septic condition. All five of these specimens show multiple papillary involvement, with yellowish to brownish streaks running in converging lines toward the tip of the papilla. Microscopically are to be seen marked tubular damage and massive deposits of calcium phosphates and some urates. We recognize in this a picture similar to that originally described by Henle and thought by him to be (tubular) calcium infarction; a view later modified by Lubarsch who showed that the calcium deposition was also extratubular. Neither of these authors in any way attributed his observations to be related to renal calculus formation; but it is to be recorded that one of our cases in this group had two small renal calculi, composed of calcium phosphate, attached to separate papillae. We concluded, therefore, that though this group represents a rarer form of papillary pathology, it nevertheless is essentially the same process and is related to the origin of renal calculus.
With this interpretation of the pathology as unfolded on microscopic study, our researches naturally led to an effort to determine the basic cause for such degenerative changes. We are not ready, at present, to draw any conclusions from these studies, but the picture would not be complete unless mention were made of our ideas and the direction of our efforts. First, by reverting to the five theories relative to stone origin, we have undertaken to try to produce hyperparathyroidism by the giving of parathormone, and a group of dogs are undergoing such administration, to be sacrificed at selected intervals and their renal papillae studied. Secondly, a large group of rats are on vitamin A deficient diets, who are to be sacrificed at earlier intervals than in other studies, in order to determine the possible occurrence of early lesions. Thirdly, the role of infection per se is to be studied, both as to specific organisms and in further tissue studies which we are watching, but we are particularly interested in certain phases of toxin action as divorced from actual tissue infection. It will be of the greatest interest to see which, if any or perhaps all, of these previously suspected etiologic factors play a part in causing the initiating lesion which we are describing.
(1) An hypothesis has been formulated that renal calculus formation is dependent upon a preexisting renal lesion. Our studies conclusively point out that this is true, and that calculo-genesis is but a symptom of some form of renal papillary damage antedating the deposition of crystalline urinary salts.
(2) This hypothesis placed the expected lesion upon the renal papilla. Microscopic studies have shown a hitherto unrecognized papillary lesion, consisting of the deposition of calcium in the walls and intertubular spaces of the renal papilla, which lesion has been observed in 17 per cent of the 429 pairs of kidneys studied at autopsy.
(3) To date, 28 specimens of renal calculus formation have been observed as growing upon, and actually adherent to, the renal papilla.
(4) In seven specimens we have been able to prove conclusively that the calculus was intimately attached to this calcium deposit, and to show that once the calcium deposit lost its epithelial covering it was subjected to a constant bath of calyceal urine, from which it is naturally assumed that crystals were deposited as upon any foreign body.
(5) We report the positive evidence that cases of calcium phosphate stone and of calcium oxalate stone have been proven to grow from such calcium plaque formation, and that in each of these cases the salt deposited as a calculus was of different chemical character from the plaque to which it was attached.
(6) It is shown that such calcium plaques appear to be a natural reparative process to some form of tubule damage, the occurrence of which is in much higher incidence than the actual clinical frequency of renal stone.
(7) The most significant conclusion to be drawn from this research is that the answer to the secret which has shrouded in mystery the true etiology of primary renal calculus is to be sought in an increasing knowledge of the physiology and pathology of the renal papilla.
Cite this page: Hill, M.A. (2021, April 12) Embryology Paper - The origin and growth of renal calculi (1937). Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Paper_-_The_origin_and_growth_of_renal_calculi_(1937)
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