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A Consideration of the Development of Polycystic Kidney
A CONSIDERATION OF THE DEVELOPMENT OF POLYCYSTIC KIDNEY CHARLES MORGAN McKENNA
AND
OTTO F. KAMPMEIER
Departments of Urology and Anatomy, from the University of Illinois, College of Medicine, Chicago, Illinois
There are many theories which begin as logical deductions, and later without foundation of observation are handed down from textbook to textbook and from paper to paper as facts. Such a one is the hypothesis of the origin of cystic kidney. When the embryologists discovered that the ureter, renal pelvis, and the collecting ducts of the kidney, on the one hand, and the uriniferous tubules to its cortex, on the other, spring from two different sources, the former as an outgrowth of the caudal end of the mesonephric or Wolffian duct, and the latter from the mesenchymal nephrogenic blastema into which the ureteric bud grows and sprouts, and that as the uriniferous tubules "crystallize" and take form in the blastema they unite with the developing collecting ducts, what was simpler and more logical than to assume that occasionally such union may fail to occur and that the uriniferous tubules continuing their functional differentiation swell out more and more with their secretions. Though the writer cannot present observations to disprove this possibility, he has perused the literature in vain for a statement of established ev-idence. On the contrary, he has shown (1923-1924) that some of the early generations of uriniferous tubules joining normally the corresponding collecting ducts break away from them again and undergo degeneration during the later developmental stages of the kidney. This phenomenon is not a sporadic one; every human being passed such a phase during his embryonic life and it is no less characteristic than the physiologic umbilical hernia, for example, which is transitory during embryonic existence. During the remaining few minutes an attempt will be made to review as simply and concisely as possible the evidence from an extensive investigation of an involved subject. It has long been known that some twelve or more orders or generations of collecting tubules are established by repeated branching and rebranch37
38
C. M. McKENNA AND 0. F . KAMPMEIER
ing of the primary outgrowths from the primitive ureteric bud. It is also well known that the nephrogenic blastema, which originally caps the ureteric bud, becomes divided and subdivided into smaller masses from which form the individual uriniferous tubules that early establish connection with the corresponding branches or generations of collecting tubules. It is generally stated that the first uriniferous tubules to be formed belong to the fourth or fifth generation of collecting ducts,in other words that the first three or four generations of collecting ducts are devoid of such tubules. Doubtlessly, this belief arose when it was found that the first few generations of collecting ducts widened and became incorporated in the expanding renal pelvis to form its calyces; for if such is the case, why should there be uriniferous tubules belonging to them? The seeming correctness of this conclusion was supported by the knowledge that no uriniferous tubules open directly into renal pelvis or calyces. But the writer has shown the error of such conclusions. The actual sequence of events is indicated by a relatively simple diagram (fig. 1), constructed after an intensive study of serial sections of kidneys of many human embryos and fetuses of different ages. Here it is clearly pointed out that there are uriniferous tubules for every generation of collecting ducts,-in other words, that already when the first collecting ducts sprout from the primitive renal pelvis, a corresponding generation of uriniferous tubules emerge from the surrounding nephrogenic blastema. These tubules, the first to appear, lie adjacent to the renal pelvis, as depicted in the diagram, and differ from all succeeding generations of tubules in that they are .vestigial from the beginning. They generally appear stunted and misshapen, many possess no glomerulus, they rarely join the neighboring primary collecting ducts, and except infrequently, disappear later without leaving a trace. Because of their character, the writer has termed the area immediately around the pelvis of the embryonic kidney in which they lie as the "vestigeal zone" (as shown in fig. 1). The next two or three tiers or generations of uriniferous tubules (fig. 1), corresponding to the second to the fourth branchings of the collecting ducts, become normally established, possess well-formed coils and glomerulus, and early unite with the collecting ducts. But after a short period they separate from them, some of them expand cystically to several times their original size, and then usually collapse and disappear. These events precede or are synchronous with the widening of the col-
DEVELOPMENT OF POL YCYSTIC KIDNEY
39
lecting ducts for their incorporation into the expanding renal pelvis. Accordingly, the writer has called this zone of the developing kidney the "provisional zone" of uriniferous tubules (see fig. 1). The third or outermost zone of the developing kidney may be termed the "growth zone," for here is established the definitive cortex (fig. 1) Here, all urinferous tubules which are developed in association with the orders of collecting ducts persist as normally functioning tubules throughout life.
FIG.
1.
THE VESTIGIAL ZONE, THE PROYISIONAL ZONE, THE GROWTH ZONE
Returning again to the forms which the early or doomed generations of uriniferous tubules take, we may refer first to the second picture (fig. 2) which illustrates reconstructions of different tubules of the first or vestigeal generation. Note their great diversity in shape and size, unmistakeable signs of their degenerative character. Sometimes these regressive tubules may undergo cystic enlargement, as shown in the next picture particularly tubule, d.
40
FIGS.
C. M. MCKENNA AND 0. F. KAMPMEIER
2
AND
3.
THE RECONSTRUCTIONS OF TUBULES IN THE VESTIGIAL GENERATION
FIG.
4.
CYSTIC ENLARGEMENTS
DEVELOPMENT OF POL YCYSTIC KIDNEY
41
Of the next two or three tiers or generations of uriniferous tubules, that is, those of the provisional zone, many are subject to cystic degeneration. In the fourth picture (fig. 4), a reconstruction of a tubule (a) . when it is still joined to its collecting duct, should be compared with its condition (d) after it has broken loose from it. In section (fig. 5), the cystic condition of such tubules is even more striking when contrasted with the tubules of normal size in the vicinity. these cystic tubules will later collapse and vanish, but occasionally one or more may persist throughout life. Such have been traced throughout embryonic and later fetal life, and they occur in infants and in adults
FrG.,
5.
A FURTHER CYSTIC CONDITION OF THE TUBULES
Such solitary cysts of the kidney are of varying size,-from that of a small pea to that of a marble and more. If we have definitely established the genetic origin of solitary renal cysts, what can we say about the genesis of multiple cysts,-that polycystic kidney. For this, the writer has been unable to secure a continuous chain of evidence. In another section all of the tubules in the provisional zone, that is those of the renal cortex nearest the renal pelvis, show cystic enlargement or the beginning of it. Should all of these tubules which have entered the initial phases in cystic formation continue to grow and distend at the same time, it is conceivable how the increasing pressure upon neighboring normal tubules would
42
C. M. McKENNA AND 0. F. KAMPMEIER
interfere with their normal genetic course and confluences, and accordingly subject a greater number of them to the same alteration until the entire or greater part of the kidney is affected. Which factor controls the normal degeneration and suppression of redundant structures is obscure. That such a factor exists seems to be indicated by the fact that the abnormal growth of some structures which should normally disappear, or undergo reduction or at any rate remain passive, may not only occur in one but in several organs as witnessed by the frequent association in the same individual of renal, hepatic, pancreatic, or genital cysts. CASE REPORT
J. K., white, aged thirty-five years, an automobile service man, was admitted to Cook County Hospital, August 4, 1932, complaining of severe pain in the left side of his back and in the left side of his abdomen, and passing blood in the urine. The patient stated that about eight hours before admittance to the hospital he had had a scuffle and during the exercise was thrown across a bed. He stated that immediately upon being thrown across the bed he experienced severe pains in the left side of his back. This pain became increasingly severe as also did the pain in the left side of the abdomen. About two hours following the injury the patient stated that he noticed what he thought was blood in the urine. He had no other complaints. His past history, both medical and surgical was negative. Physical examination revealed a white male, fairly well nourished and fairly well developed, who was apparently acutely ill and in extreme pain. Superficially there were numerous scratches and abrasions about the skin of the chest, arms, back and abdomen. The pupils were contracted, the conjunctivae were very pale. The heart was not enlarged, the heart tones were of fair quality, regular, and there were no murmurs or pericardia! friction rubs. The lungs presented no abnormalities. The abdcmen was distended. The entire left half of the abdomen was rigid. This was especially true of the upper half; this area also presented a rounded, bulging area which was fairly firm upon palpation and extremely tender. No intra-abdominal organs were palpable. There were no abnormal or pathologic reflexes elicited. The radial arteries were soft and smooth, readily compressible, pulse 110, regular, fair volume and equal on both sides. Blood pressure was 100/80 on both arms with the patient reclining. The blood count revealed a 68 per cent hemoglobin, 4,000,000 red cells, 12,500 white cells and a coagulation time of 3.5 minutes.
DEVELOPMENT OF POL YCYSTIC KIDNEY
I
.l
d
43
The urine was acid, specific gravity 1.028, albumin 4 plus, sugar negative, microscopic field covered with red blood cells. I saw the patient about si_x hours after admittance and made a tentative diagnosis of (a) probable extracapsular tear of the left kidney with reflex anuria, or (b) rupture of the left kidney. I advised that an intravenous pyelogram (Skiodan) be made. This was done, and the result was good . Blood chemistry showed a urea nitrogen of 27 .55 mgm. per 100 cc. of blood. Creatinin was 2.1 mgm. per 100 cc., and sugar, 52.63 mgm. The Kahn test was negative. On August 5, 1932, the patient was operated upon and the left kidney was removed. The kidney upon being exposed was enveloped in a mass of dark red, clotted blood; the amount of blood was estimated at 500 to 600 cc. Nephrectomy was carried out in the usual manner, two gauze drains were placed in the kidney fossa, and the wound was closed. Grossly, this kidney was 24 by 10 by 11 cm., and almost completely converted into a mass composed of multilocular. cysts, which ranged from the size of a common pin head to 3 cm. in diameter. There was practically no renal parenchyma intact. The cysts were filled with a clear fluid. The specimen also presented three recent lacerations, one in the upper pole of the kidney, one in the lower pole, and one in the region of the hilus. These lacerations varied from 1 to 3 cm. in length, and the deepest one would admit onehalf the length of the little finger. Microscopically, the kidney was made up of multiple cysts which were lined by a single layer of epithelium. The intervening tissue was composed of compressed renal cortex and medulla. Pathologic diagnosis was congenital polycystic kidney with recent lacerations. Following the operation, the patient progressed satisfactorily until the thirteenth postoperative day, when he developed a toxic psychosis from which he recovered. He was discharged as improved on September 9, 1932.
1405 Marshall Field Annex, Chicago, Illinois
AND
OTTO F. KAMPMEIER
Departments of Urology and Anatomy, from the University of Illinois, College of Medicine, Chicago, Illinois
There are many theories which begin as logical deductions, and later without foundation of observation are handed down from textbook to textbook and from paper to paper as facts. Such a one is the hypothesis of the origin of cystic kidney. When the embryologists discovered that the ureter, renal pelvis, and the collecting ducts of the kidney, on the one hand, and the uriniferous tubules to its cortex, on the other, spring from two different sources, the former as an outgrowth of the caudal end of the mesonephric or Wolffian duct, and the latter from the mesenchymal nephrogenic blastema into which the ureteric bud grows and sprouts, and that as the uriniferous tubules "crystallize" and take form in the blastema they unite with the developing collecting ducts, what was simpler and more logical than to assume that occasionally such union may fail to occur and that the uriniferous tubules continuing their functional differentiation swell out more and more with their secretions. Though the writer cannot present observations to disprove this possibility, he has perused the literature in vain for a statement of established ev-idence. On the contrary, he has shown (1923-1924) that some of the early generations of uriniferous tubules joining normally the corresponding collecting ducts break away from them again and undergo degeneration during the later developmental stages of the kidney. This phenomenon is not a sporadic one; every human being passed such a phase during his embryonic life and it is no less characteristic than the physiologic umbilical hernia, for example, which is transitory during embryonic existence. During the remaining few minutes an attempt will be made to review as simply and concisely as possible the evidence from an extensive investigation of an involved subject. It has long been known that some twelve or more orders or generations of collecting tubules are established by repeated branching and rebranch37
38
C. M. McKENNA AND 0. F . KAMPMEIER
ing of the primary outgrowths from the primitive ureteric bud. It is also well known that the nephrogenic blastema, which originally caps the ureteric bud, becomes divided and subdivided into smaller masses from which form the individual uriniferous tubules that early establish connection with the corresponding branches or generations of collecting tubules. It is generally stated that the first uriniferous tubules to be formed belong to the fourth or fifth generation of collecting ducts,in other words that the first three or four generations of collecting ducts are devoid of such tubules. Doubtlessly, this belief arose when it was found that the first few generations of collecting ducts widened and became incorporated in the expanding renal pelvis to form its calyces; for if such is the case, why should there be uriniferous tubules belonging to them? The seeming correctness of this conclusion was supported by the knowledge that no uriniferous tubules open directly into renal pelvis or calyces. But the writer has shown the error of such conclusions. The actual sequence of events is indicated by a relatively simple diagram (fig. 1), constructed after an intensive study of serial sections of kidneys of many human embryos and fetuses of different ages. Here it is clearly pointed out that there are uriniferous tubules for every generation of collecting ducts,-in other words, that already when the first collecting ducts sprout from the primitive renal pelvis, a corresponding generation of uriniferous tubules emerge from the surrounding nephrogenic blastema. These tubules, the first to appear, lie adjacent to the renal pelvis, as depicted in the diagram, and differ from all succeeding generations of tubules in that they are .vestigial from the beginning. They generally appear stunted and misshapen, many possess no glomerulus, they rarely join the neighboring primary collecting ducts, and except infrequently, disappear later without leaving a trace. Because of their character, the writer has termed the area immediately around the pelvis of the embryonic kidney in which they lie as the "vestigeal zone" (as shown in fig. 1). The next two or three tiers or generations of uriniferous tubules (fig. 1), corresponding to the second to the fourth branchings of the collecting ducts, become normally established, possess well-formed coils and glomerulus, and early unite with the collecting ducts. But after a short period they separate from them, some of them expand cystically to several times their original size, and then usually collapse and disappear. These events precede or are synchronous with the widening of the col-
DEVELOPMENT OF POL YCYSTIC KIDNEY
39
lecting ducts for their incorporation into the expanding renal pelvis. Accordingly, the writer has called this zone of the developing kidney the "provisional zone" of uriniferous tubules (see fig. 1). The third or outermost zone of the developing kidney may be termed the "growth zone," for here is established the definitive cortex (fig. 1) Here, all urinferous tubules which are developed in association with the orders of collecting ducts persist as normally functioning tubules throughout life.
FIG.
1.
THE VESTIGIAL ZONE, THE PROYISIONAL ZONE, THE GROWTH ZONE
Returning again to the forms which the early or doomed generations of uriniferous tubules take, we may refer first to the second picture (fig. 2) which illustrates reconstructions of different tubules of the first or vestigeal generation. Note their great diversity in shape and size, unmistakeable signs of their degenerative character. Sometimes these regressive tubules may undergo cystic enlargement, as shown in the next picture particularly tubule, d.
40
FIGS.
C. M. MCKENNA AND 0. F. KAMPMEIER
2
AND
3.
THE RECONSTRUCTIONS OF TUBULES IN THE VESTIGIAL GENERATION
FIG.
4.
CYSTIC ENLARGEMENTS
DEVELOPMENT OF POL YCYSTIC KIDNEY
41
Of the next two or three tiers or generations of uriniferous tubules, that is, those of the provisional zone, many are subject to cystic degeneration. In the fourth picture (fig. 4), a reconstruction of a tubule (a) . when it is still joined to its collecting duct, should be compared with its condition (d) after it has broken loose from it. In section (fig. 5), the cystic condition of such tubules is even more striking when contrasted with the tubules of normal size in the vicinity. these cystic tubules will later collapse and vanish, but occasionally one or more may persist throughout life. Such have been traced throughout embryonic and later fetal life, and they occur in infants and in adults
FrG.,
5.
A FURTHER CYSTIC CONDITION OF THE TUBULES
Such solitary cysts of the kidney are of varying size,-from that of a small pea to that of a marble and more. If we have definitely established the genetic origin of solitary renal cysts, what can we say about the genesis of multiple cysts,-that polycystic kidney. For this, the writer has been unable to secure a continuous chain of evidence. In another section all of the tubules in the provisional zone, that is those of the renal cortex nearest the renal pelvis, show cystic enlargement or the beginning of it. Should all of these tubules which have entered the initial phases in cystic formation continue to grow and distend at the same time, it is conceivable how the increasing pressure upon neighboring normal tubules would
42
C. M. McKENNA AND 0. F. KAMPMEIER
interfere with their normal genetic course and confluences, and accordingly subject a greater number of them to the same alteration until the entire or greater part of the kidney is affected. Which factor controls the normal degeneration and suppression of redundant structures is obscure. That such a factor exists seems to be indicated by the fact that the abnormal growth of some structures which should normally disappear, or undergo reduction or at any rate remain passive, may not only occur in one but in several organs as witnessed by the frequent association in the same individual of renal, hepatic, pancreatic, or genital cysts. CASE REPORT
J. K., white, aged thirty-five years, an automobile service man, was admitted to Cook County Hospital, August 4, 1932, complaining of severe pain in the left side of his back and in the left side of his abdomen, and passing blood in the urine. The patient stated that about eight hours before admittance to the hospital he had had a scuffle and during the exercise was thrown across a bed. He stated that immediately upon being thrown across the bed he experienced severe pains in the left side of his back. This pain became increasingly severe as also did the pain in the left side of the abdomen. About two hours following the injury the patient stated that he noticed what he thought was blood in the urine. He had no other complaints. His past history, both medical and surgical was negative. Physical examination revealed a white male, fairly well nourished and fairly well developed, who was apparently acutely ill and in extreme pain. Superficially there were numerous scratches and abrasions about the skin of the chest, arms, back and abdomen. The pupils were contracted, the conjunctivae were very pale. The heart was not enlarged, the heart tones were of fair quality, regular, and there were no murmurs or pericardia! friction rubs. The lungs presented no abnormalities. The abdcmen was distended. The entire left half of the abdomen was rigid. This was especially true of the upper half; this area also presented a rounded, bulging area which was fairly firm upon palpation and extremely tender. No intra-abdominal organs were palpable. There were no abnormal or pathologic reflexes elicited. The radial arteries were soft and smooth, readily compressible, pulse 110, regular, fair volume and equal on both sides. Blood pressure was 100/80 on both arms with the patient reclining. The blood count revealed a 68 per cent hemoglobin, 4,000,000 red cells, 12,500 white cells and a coagulation time of 3.5 minutes.
DEVELOPMENT OF POL YCYSTIC KIDNEY
I
.l
d
43
The urine was acid, specific gravity 1.028, albumin 4 plus, sugar negative, microscopic field covered with red blood cells. I saw the patient about si_x hours after admittance and made a tentative diagnosis of (a) probable extracapsular tear of the left kidney with reflex anuria, or (b) rupture of the left kidney. I advised that an intravenous pyelogram (Skiodan) be made. This was done, and the result was good . Blood chemistry showed a urea nitrogen of 27 .55 mgm. per 100 cc. of blood. Creatinin was 2.1 mgm. per 100 cc., and sugar, 52.63 mgm. The Kahn test was negative. On August 5, 1932, the patient was operated upon and the left kidney was removed. The kidney upon being exposed was enveloped in a mass of dark red, clotted blood; the amount of blood was estimated at 500 to 600 cc. Nephrectomy was carried out in the usual manner, two gauze drains were placed in the kidney fossa, and the wound was closed. Grossly, this kidney was 24 by 10 by 11 cm., and almost completely converted into a mass composed of multilocular. cysts, which ranged from the size of a common pin head to 3 cm. in diameter. There was practically no renal parenchyma intact. The cysts were filled with a clear fluid. The specimen also presented three recent lacerations, one in the upper pole of the kidney, one in the lower pole, and one in the region of the hilus. These lacerations varied from 1 to 3 cm. in length, and the deepest one would admit onehalf the length of the little finger. Microscopically, the kidney was made up of multiple cysts which were lined by a single layer of epithelium. The intervening tissue was composed of compressed renal cortex and medulla. Pathologic diagnosis was congenital polycystic kidney with recent lacerations. Following the operation, the patient progressed satisfactorily until the thirteenth postoperative day, when he developed a toxic psychosis from which he recovered. He was discharged as improved on September 9, 1932.
1405 Marshall Field Annex, Chicago, Illinois