Renal Agenesis and Dysgenesis

THE .JOl::R~AL OF UROLOGY

Vol. 83, Ko. 3, March 1960 Printed in U.S.A.

REl\AL A.GENESIS A~D DYSGENESIS DAVID J. B. ASHLEY*

AXD

F. K. MOSTOFI

From the Anneci Forces Institute of Pathology ancl Veterans Adnrinislralion Centrnl Lahoralor11 for Anato1nicaJ Pathology ancl Research, Washington 25, D. C

This work is confined to a conditions of renal agcnesis and c;C\'ere both unilateral and bilateral, ,vith an tion bf the associated defects of the tract and of the other organs.

The seience of embryology has advanced from the stage of a purely d0scriptivc discipline, to that of an experimental one, and the major problems facing us today are those of the interaction between the parts of the embryo and the effects of such interactions on the subsequent development of the individual. l\Iost of the work in this field has Imel, perforce, to be clone on the lower, oviparous, animals in which it is possible to operate on the egg at an early stage of development without interfering with the later growth ancl differentiation of the animal. In the case of the Eutheria, such methods are hardly possible, although Jost a and h) has performed many most interesting experi-ments on the intra-uterine embryos of rabbits. The second disadvantage of this type of experimentalism in the present state of technical skill is that the methods uscd to affect the future life of the embryo must be relatively crude and may cause severe and widespread c~ffects on the organism even when apparently minimal lesions arc produced in the early embryo. Furthermore, especially in the case of the larger mammals, the stage of development which is most interesting from the point of view of organ growth and differentiation is ,'ery early, and most of the organs have undergone the major part of their differentiation before the mother is aware with certainty that she is pregnant at a!L Fortunately, there is another line of attack on this problem. Anomalies of organ development are seen in which failure of growth or abnormal growth has taken and, by comparison with the normal mode of differentiation set forth the descriptive embryologists, the ,mquence of events in normal growth ancl the dependence of one part upon another can be elucidated. For this reason, a fresh study of the congenital anomalies of the renal tract has been undertaken.

OllSKRVAT!O,';S

Three hundred ancl sixty-four cases from tlw files of the A.rrned Forces Institute of were studied. ,\!most all were of had died, sometimes from causes rnm1ec:ted with their anomaly and sometimes from entirely extram;ous causes. If no rnstigc o/ rcn:11 tissue was detected, the anomaly \l'a~ callr,d agenesis; if the kidney was ""''""''"" a nodule of tissue bearing no histological resemblance to normal renal pan'n-chyma, the state was designated wbile the term hypoplasia mm rcserwci for cases having a kidney that was small but othcc wise similar to the normal organ. The basic data in these cascs are snt out table 1. The cases were taken from tt ,:olledinn of 245,000 autopsy protocols and related ~lidr\'J in the files of the Armed Forces Tnstitute of Pathology. The incidence of anomalies is, therefore, of the order of J in responds with the figure of Bell 519, bearing in mind the high cases which are received from military source2. Similarly, the proportions of males a.nd except in the cases of bilateral bilateral clysge1wsis, represent tlw of the population from which the matnial. wac obtained rather than the true se:s-; im:iden,,e of the conditions. As in the series rollectecl Collins ('32) from the literature, the left side was more commonly involved in tlw case., of unilateral anomaly than the right. No infrrence can be drawn from the relative the various types of defect, as it is years that num? casc;s of neonatal death hn.ve been included in the material sent for acce.,sion. Two hundred ancl thirty-two ca~c,s were .S(;en m which there was l'.Omplctc absence of

Aecepted for publication July 16, 1D59.

* This work was done while Dr. Ashlev was at the

as

Armed Forces Institute of Pathology a Special Research Fellow sponsored by the Dillon Project of the Memorial Center for Neoplastic and Allied Diseases, New York City 211

212

D. J. B. ASHLEY AND F. K. MOSTOFI

kidney on one side, and in 47 cases no kidney was found on either side. Sixty-eight instances of dysgenesis of the kidneys were seen. Of these, 57 were unilateral and 11 bilateral; in one of the latter the rudimentary kidneys were fused and in the midline. In 9 cases the anomaly was mixed: there was a dysgenetic kidney on one side and no renal tissue on the other. The remaining 8 cases all showed crossed renal ectopia; on one side no kidney was found at all, and on the other there was a double kidney with two ureters. Age distribution. The age at death or, in the rare surgical cases, at the time of diagnosis was known in all but nine of the cases (table 2). One hundred and twenty-three, including all the 68 with bilateral anomalies, were under the age of 10 years, and 133 were between the ages of 10 and 85. This age distribution is not to be regarded as of great significance except insofar as it indicates that the unilateral defects in the TABLE

1. Types of renal anomaly encountered in

the present series Renal Anomaly

Unilateral agenesis. Unilateral dysgenesis Bilateral agenesis .. Bilateral dysgenesis. Crossed ectopia. Agenesis one side, dysgenesis other side.

Total Male Female Right Left -- - - -- --

232 57 47 11 8

9

210 52 32 5 8

6

22 5 15 6 -

3

100 26

132 31

-

-

-

-

4

4

6

3*

----------- - - -- --- - - --

Totals.

364

313

51 1136 170

* Side of agenesis. TABLE

kidney are in no way incompatible with normal life to an advanced age. The high proportion of relatively young men in the group of unilateral agenesis is to be explained by the military nature of the population from which this study was drawn. The incidence of immaturity was studied in the stillborn children and those who died in the first few days of life (table 3). The dividing line was set at the usual weight of 2,500 gm.; those babies weighing less than this amount were regarded as immature. The incidence of immaturity was much higher in the group of bilateral renal anomalies than in the group of unilateral anomalies, which are usually compatible with a prclonged period of extra-uterine life; only 6 out of 62 in the former group were of the larger size, whereas almost half (21 out of 43) of the latter were mature. Cause of death. All but five of the patients in this study were dead. This is merely an indication of the severity of the defect in the cases of bilateral kidney deficiency, which is incompatible with continued extra-uterine life, and of the relative lack of symptoms associated with the presence of an anomaly of one kidney, which is perfectly compatible with life and which is, therefore, commonly only detected at autopsy. Nineteen of the patients with bilateral anomalies were stillborn, and 48 died within the first few days of life because of their congenital anomalies. The cause of death in the cases of unilateral anomalies of the kidney is set out in table 4. Seventeen of them were stillborn or died in infancy from causes unconnected with the renal anomaly, 32 had associated anomalies which

2. Age distribidion of patients with renal anomaly Age

Renal Anomaly

Unilateral agenesis. .... Unilateral dysgenesis. .. . Crossed ectopy. Bilateral agenesis .. Bilateral dysgenesis .. Mixed anomaly.

Less 1 Still- than Not 1 month 1 to 11 to 21 to 31 to 41 to 51 to 61 to 71 to Over born month to 1 yr. 10 yr. 20 yr. 30 yr. 40 yr. 50 yr. 60 yr. 70 yr. 80 yr. 80 yr. stated ------ -- -- -- -- -- -- -- -- --

7 2 1 15 2 2

24 -

13 3

1 -

10 1

37

30

10

10

24 4 2

42 11

25 9

9 2

4 2

6 3 -

2 3 --32 9 7 ------------- -- -- ---- ---- -- -- ----Totals ................... 29 16 1 11 49 40 53 -;-4-[~1- 6 75 30 9 . .

-

-

RE-"
TABLE

3. Birth weight of babies with renal anomaly*

I

iUnt,~!~00 2,;~~ g~~~s

Renal Anomaly -------------

Unilateral agenesis _ Unilateral dysgenesis. Crossed ectopia. Bilateral agenesis. Bilateral dysgenesi s _. Mixed anomaly.

,

-----

17 2 I I I

. . .I

-----

18 2

3 43

2

10 ;:i

4

1

* In 15 instances the birth weight was not stated in the autopsy protocol.

were incompatible with life, and the remainder died of a variety of conditions such as would be expected in any group of unselected autopsies. The incidence of renal disease as a cause of death was, however, high; 54 of the 293 patients in this group had renal disease, as opposed to renal anomaly, as a major factor in the causation of death. The types of renal disease seen arc set out in table 5. In some of these cases, there was concurrent structural malformation of the contralatcral kidney, although there was adequate renal tissue available for normal excretion. In seven, the opposite kidney was located in the pelvis; in 12, there was hydroureter on the opposite side; in 10, the opposite kidney contained cysts; and in five there were anomalies of the ureters on the opposite side. The ureteric anomalies seen were: two cases with double renal pelves and bificl ureters; two with double pelves and ureters, in one of which the extra ureter opened into the bladder on the same side as the true ureter for the kidney, and in the other, the abnormal ureter drained into the verumontanum; in the final case, the ureter drained into the seminal vesicle of the same side. The incidence of renal disease was much higher in the group with dysgenesis of one kidney than in that with complete absence of one kidney" The distribution of the types of renal lesion between these two groups was similar, and the incidence of minor anomalies of the other kidney was almost the same in both. Anatomical abnormalities. Renal arteries: The renal arteries were absent on the side of the renal abnormality in 76 of the cases of complete renal agenesis. In 1 case only there was a minute vessel emerging from the aorta at the site from which a normal blood vessel to the kidney \\'Ould be expected. Eleven of the cases of

clysgenesis of the kidney showed abo absence u! the renal artery on the homologous am! two instances there was a small ves~el with n minute lumen running to the rudimentary kidne)'. In the cases of bilateral renal absence of the renal vessels ,ms noted in l I, and in two of the cases of bilateral the vessels were also noted as absento Three of tlw examples of crossed renal ectopia wen' ported as having no vessrl on the side to that On which the fused kiclne \°R WCn' 0

TABLE

4. Cau.ses of death in cases of uni"lnleml

renal anomaly Ag~nes1s

Immaturity. Stillbirth and fetal anoxia. Asphyxia neonatorum. Acute respiratory infection. Congeni ta! ma! formations .. Injury. Pulmonary disease. Malignant tumor. Renal disease. Central nervous system disease. Heart disease . Tuberculosis. Gastrointestinal disease. Other.

7

4 2 2 2!}

29

7

10

4

43

10 17

36

13 ;30 7 11

7 2

2

8

2:n

7

Surgical specimens from patients still living. Totals.

TABLE

5. Types of renal disease seen m cases -nnilaieral renal anomaly Renal Disease

Acute pyelonephritis .. Chronic pyeloncphritis. Sub acute glomcrulonephri tis. Chronic glomerulonephritis. N ephrosclerosis .. Sucrose nephrosis . Totals.

* Two were malignant nephrosclerusi,,.

214

D. J. B. ASHLEY AXD F. K. MOSTOFI

and in two of the cases with absence of one kidney combined with dysplasia of the other, there was no renal vessel on the side of the agenesis. In many autopsy reports, there was no mention of the state of the renal vessels. In a total of 108 autopsies in which this information was available, however, there was no case in which a major renal vessel was seen in conjunction with an absent or grossly deficient kidney; and, in general, the smaller the remnant of kidney tissue, the more likely was the renal vessel to be completely absent. Ureters: The presence or absence of the ureter and the extent to which it has developed are most important factors in an understanding of ontogenesis of defects in renal development. Information on this point was available in the majority of the cases studied here. unilateral agenesis: The ureter corresponding to the affected kidney was completely absent in 138 cases, and in 19 other cases only a portion of the lower end of the ureter was present. In no instance was there a fully developed ureter reaching up to the site at which normal kidney would be found. In 123 of the cases with completely absent ureters, examination of the bladder showed that the ureteric orifice of the affected side and part of the trigone had failed to develop. The partly developed ureters varied in size and in the degree of their maturation. In eight, the fragment of ureter was less than 10 cm. long. In nine, it was longer than 10 cm. It was usually patent and of normal caliber but ended blindly at its upper end. In 2 cases, the partly developed ureter was patent but did not open into the bladder. In one of these, the opening was in the urethra at the level of the verumontanum, and in the other it was into the seminal vesicle on the affected side. Bilateral agenesis: There was complete absence of both ureters in 39 of the cases of bilateral renal agenesis, and partial absence in three. The ureteric orifices were also absent in 20 of the cases of complete ureteric agenesis, and the bladder was either absent altogether or consisted only of a muscular tube with a minute lumen in the other 19. In the three cases with partial absence of the ureters, small projections adjacent to the side of the bladder were seen, but no normal hollow structure. Unilateral dysgenesis: In 37 of the cases of

unilateral renal clysgenesis, the ureters were noted to be present and patent up to the rudimentary kidneys. In 4 cases, the prosector had searched for the ureter and had failed to find any vestige of one, despite the presence of a nodule of tissue in the site of the kidney which contained the histological elements characteristic of malformed kidney. In 1 case, the ureter was present only at the lower encl, consisting of a patent tu be 10 cm. in length. It was noted that the ureter was absent and that there was no ureteric orifice in one case, a surgical specimen. This case is not used in the argument, as there may have been an ectopic orifice. In 11 other cases, the ureter was fibrotic and contained either a minute lumen or no lumen at all. The site of insertion of the ureter was noted to be anomalous in 3 cases, two opening into the seminal vesicle of the homolateral side and one into the posterior urethra. In six additional cases it was noted that the ureteral orifice in the bladder was not present. In one of these cases, the ureter was partially absent and was represented only by a small fragment of tissue at the bladder neck; in two the ureter consisted only of a fibrous cord with no lumen; three were cases of complete absence of the ureter. Bilateral dysgenesis: Both ureters were present and patent up to the level of the renal masses, in eight of the 11 cases of bilateral renal dysgenesis. In the other 3 cases, the ureters could not be identified at autopsy, and in two of them, the ureteric orifices and the trigone of the bladder were also absent. Crossed renal ectopia: In all 8 cases of crossed renal ectopia, both ureters were present, although in each case the ureter from the lowermost pole of the fused kidney crossed the midline and was inserted into the bladder at the site for a normal ureter from the side of the absent kidney. Mixed anomalies: In the 9 cases showing agenesis of the kidney on one side with dysgencsis of the organ on the other side, there was a wide range of appearance of the ureters. On the side of the renal agenesis, the ureters were completely absent in 8 cases, and there was a small fibrous remnant in the remaining case. The cases of complete ureteric absence showed also absence of the associated ureteric orifice in 3 cases and absence and atresia of the bladder in 1 case each. On the side of the renal dysgenesis, the ureters were noted to be present and patent

RE:\'AL AGE:\'ESIS AXD DYSGEXESIS TABLFJ

6. Development of the adrenal glands

Renal Anomaly

Unilateral agenesis Cnilateral dysgenesis. Bilateral agenesis. Bilateral dysgenesis. Crossed ectopia. :\Iixed anomaly. Totals ..

i

Both Present

HH

romol

Not

l9

22 5 3

_A~~~~t Stated

52

44 10 6 8

311

dcr on that side, and in one, the state of ( be, bladder was not mentionecl. ln one' rase of rena !

1 1*

21

l 1

32

* Side of absent kidney

in 2 cases, to be represented only by a fibrous cord in 5 cases, and to be absent in 2 cases. In two of the cases in which the ureter was fibrotic, it was noted that only the upper end of the ureter was present and that there ,vas no connection with the pelvic structures. The patient with no bladder also showed no ureter to the aplastic kidney, and the patient with an atretic bladder hacl a fibrous atretie ureter on the side nf the renal aplasia. The 2 eases in which the ureter to the dysgcnetic kidney was absent had no ureteric orifice on either side. No anomalies of insertion of the urPtern were seen in this group of cases. Adrenals: Both adrenal glands were present in the majority of the cases in this study. In 21 cases the adrenal was ab8ent, and in 31 the protocol mad<' no mention of the presence or absence of the glancl. Nineteen of the cases with absence of the adrenal ,,·rn· among the group of unilateral renal agenesis (table one was a case of crossed renal ectopy, and in one case (of mixed anomaly) the adrenal was absent on thr side of the renal agenesis. In one of the cases of the mixed anomaly, the adrenal gland was in an almorrnal situation 011 the posterior abdominal wall inferim to the renal remnant. In 14 of the cases in ,,·hich the homolatcrnl adrenal gland was the state of the ureter to the corresponding side ,vas known. One case was of crossed renal ertopia in which the ureter was present, although draining the opposite kidney. In 12, the single case of the mixed anornal:v ancl 11 of the cases of unilateral agenethe ureter on the sidr of the absent kidney and adrenal was completely absent; in 10 of there was no uretc>ric orifice in the blarl-

agenesis, there was a segment of ureter 011 the affected side, mrasuring 20 cm. The histologieal appearance of the kidneys: Slides of thC' rudimentary kidrwy tiss11c were available in 36 instances in which tb,re had been partial failure of renal This group included 4 cases in which tlw had developed in the absence of any mdcri,·. structure. The rudimentary kidney did not, as a have the typical reniform appearance but consisted rather of a. mass of tissue, devoid structure, clustered round the uppn end of ttw ureter. In one case, however, the kidney, consisting of the usual mixture of elements, had the gross appearanc:c of a smell! kidney (fig. l). Histologically, the rPnal rudiments consisted largely of small tubules set in a connective tis:ouc stroma (fig. 2). The tubules were lined by cubical or low columnar epithelium and in some instances were dilated to form i:imall cysts In l case, the lining of some of the tubules consi~tcd of large cubical cells with clear a striking resemblance to cpididymal tubules (fig. 3). Immediately surrounding the there was charactrristically a zone of loose, immature conmcctive tissue which rn turn merged into the disorganized connedive ti.,sm',; of the renal rudiment (fig. The~c latter tissm',: consisted largely of fibrous tissue with a f('\\' strands of smooth muscle and an occasional island of cartilage (fig. 4). 1n the older there was extensive calcification of the st1·oma of the rudimentary kidney. Glomerular :,;tructures were scc'n in 6 ca8l'c'. These ranged in complexity from simple nations of the tubules to structures capillary loops and having tl close n':,cmhlancJ' to normal glomeruli (figs. fi and G). AJ] of tl1e patients in whom the renal rudiment contained these pseudoglomcruli wPre in the ycungcr age, groups. This type of strnctm was Fortune ('27) and suggests that the of the metanephric blastcma is the' formation of normal renal structure
216

D. J. B. ASHLEY AND F. K. MOSTOFI

FIG. 1. Dysgenetic kidney, reniform in shape, and containing no adult renal tissue. Hematoxylin and eosin. X5. AFIP No. 58-14041.

FIG. 2. Section of dysgenetic kidney showing small tubules in loose connective tissue stroma with some tendency to cyst formation. Hematoxylin and eosin. X115. AFIP No. 58-14039.

FIG. 3. Section showing tubules lined by tall, clear cells resembling epididymal cells. Hematoxylin and eosin. X305. AFIP No. 58-14046.

1

I

I

' Fm. 4. Island of imnrnture cartilnge in renal rudiment. Hematoxylin and eosm. )(115, /\FI_P No, 58-140:38.

Fm. 5. Tubule invaginat.ed by a connective tissue mass containing only fibrous 1issue. Hematuxyli 11 and eosin. Xl15. AFIP No. 58-14037.

Fm. 6. 1'scudoglomerulus Tuft is formed by cellular mass which includes small vessel. Henrnr.oxyln, and eosin. X305. AFIP No. 58-14047.

217

218

D. J. B. ASHLEY AND F. K. MOSTOFI

glomeruli and also indicate the ability of the kidney to form connective tissues not found in that organ in the normal state of differentiation. The tubules surrounded by undifferentiated stromal cells, morphologically resembling the cells of the endometrial stroma, serve as a further reminder of the common origin of the epithelial and connective tissue components of the kidney from the mesodermal tissue of the nephrogenic ridge. DlSCUSSION

Congenital absence and incomplete development of the kidney are by no means rare anomalies. Allen ('51) cites the incidence of bilateral agenesis as 1 in 243 stillbirths, that of unilateral agenesis as 1 in 519 individuals, that of unilateral dysgenesis as 1 in 816, and that of bilateral dysgenesis as being rather less than that of bilateral agenesis. Davidson and Ross ('54) collected a total series from the literature of 232 cases of bilateral agenesis, but no comparable compilation of the other types of congenital renal defect has recently been made. The present series is reported because the study of defects in this system throws light on many facets of embryology and because this series is probably unique, both in its extent and in the completeness of the protocols, records, and histological material on which it is based. The discussion will be based largely on the new material reported, and no attempt is made to cull the harvest of reports in the literature. Consideration of the embryological bases of the defective developments seen here may be divided into two parts. The kidney itself with the ureters and renal arteries will be considered first, with a discussion of the embryogenesis of renal defects and of defects in the closely associated sex ducts and in the structures derived from the urogenital sinus. Secondly, the defects seen in other parts of the body in association with anomalies of development of the renal tract will be considered in relation to the etiology of all these abnormalities. Morphogenesis. Anomalies of the kidneys, renal arteries and ureters: The normal morphological events in the development of the renal tract are well established and may be recapitulated very briefly. A series of three sets of tubules develops in the embryo. The first, the pronephros, appears as a set of about seven pairs of

tubules during the latter part of the third week of life. The more cranial of these tubules appear first and are already beginning to show regression as the more caudal ones are formed. The distal end of each tubule extends caudally and fuses with the end of the tubule behind it to form a continuous duct which grows beyond the tubules and enters the side of the cloaca. The mesonephric tubules begin to form in the middle of the fourth week and make contact with the pronephric duct caudal to the pronephros. With the degeneration of the pronephros, the duct becomes known as the mesonephric duct. The tubules of the mesonephros play a part in the development of the gonads of the male but have no further role in the formation of the renal system and are, in turn, absorbed. The definitive kidney of the adult is formed from two structures. A bud grows out from the mesonephric duct close to its junction with the cloaca early in the fifth week and begins to extend cranially. As it develops, the blind end dilates to form the rudiment of a renal pelvis, and a condensation of the mesoderm of the lower end of the nephrogenic ridge caudal to the lowermost mesonephric tubules forms around it. The metanephros now begins to "grow" cranially and undergoes internal structural changes. The ureteric bud ramifies to form the renal pelvis with the major and minor calyces, and some, at least, of the collecting tubules; and the cap of mesoderm becomes canalized with the formation of the glomerulus and the upper part of the nephron (Patten, '53; Arey '46). The generally accepted theory of the mechanism by which the mesoderm of the lower end of the nephrogenic ridge is induced to form renal tissue is that the ureteric bud formed by the lower end of the mesonephric duct directly stimulates the differentiation of renal parenchyma. This view is expressed succinctly by Potter ('52), who states, "A kidney never develops in the absence of a ureter." There has been much debate over the means, within this theory, by which the defect of renal development occurs. In this connection, there are many hypotheses, both of morphogenesis and of what, for want of a better term, will be called etiology. The former is discussed first, and the latter will be considered later. Radasch ('08) suggested that renal agenesis

RENAL AGENESIS AND DYSGENESIS

might be due to failure of the ureteric bud to develop; to regression of the bud; or to failure of formation of the pronephros and mesonephros, with the consequent failure of the pronephric duct, and hence the ureteric bud, to develop. Allen ('51) suggested, in addition, that there might be a deficiency of the metanephric blastema so that the ureteric bud, though fully capable of inducing differentiation, had no tissue on which to act. Another hypothesis was brought forward by Campbell ('54), who postulated that the blood vessels supplying the renal blastema might fail to form and that renal agenesis and dysgenesis might be secondary to localized fetal ischemia. The vascular hypothesis is considered unlikely, although the associated anomalies of the renal vessels lend it a certain plausibility. In general, the vessels supplying a part of the body are of such a caliber as to provide a blood supply which is adequate to the differentiated structure, and it is uncommon for vascular anomalies to be the primary cause of defects of organogenesis. Further evidence against this suggestion is that the contralateral kidney is usually hypertrophied and has a much larger blood supply than a normally sized organ. It would be difficult to accert the corollary that the renal vessel of the side opposite to that of the absent kidney should have been provided, by a beneficent providence, with a larger vessel so that the total renal parenchyma might be of normal extent. The findings in this series can be interpreted in most cases as corroborative of the earlier hypotheses of the morphogenesis of renal defect. There is, however, an important point of difference. Four cases of unilateral renal dysgenesis were seen in which there was complete absence of the ureters, and in two of these, the ureteric orifices into the bladder were also absent. One instance of unilateral dysgenesis showed partial absence of the ureters, only the lower ends being present, and in one the rudimentary kidney was removed at operation but no ureter was found. Three cases of bilateral dysgenesis of the kidneys were noted to be without ureters at all, and in two of the cases of the mixed anomaly the ureters on the side of the dysgenetic kidney were absent; in three of these five cases, there were no ureteric orifices in the bladder. These 11 cases suggest that the presence of the ureteric bud is not necessary for the kidney

219

to develop, at least in part, and that the metanephric blastema has within itself the potentiality for differentiation into a kidney, albeit one without the drainage necessary for function. The observation of an early human embryo in which the left wolffian duct had failed to reach the cloaca, but in which the left renal blastema was present and fused with that of the right side (Boyden, '32), lends support to this suggestion. Boyden ('32) also carried out experimental observations which support this view. He injured the wolffian duct in chick embryos of 36 to 56 hours of differentiation and showed that the ureter did not develop, but that even in the absence of the ureter, the renal blastema forms in the metanephric region. His experiments did not, however, follow the development of the renal blastema beyond the age of 6 days, at which time it was still present. A similar view was held by Brown ('31), who studied mice with genetic renal failure and noted that the metanephric blastema developed in cases where the ureter failed to form. The state of the suprarenal glands is also germane to the question of the mechanism by which the development of the renal tract takes place. The adrenal develops from two sources. The medulla arises from cells of the neural crest, which migrate laterally to form the sympathetic ganglia and the chromaffin bodies along the sides of the spinal column. The cortex, which invests the medulla in man, takes origin from the lateral mesoderm just cranial to the mesonephric tubules. It is first seen as a proliferation of the celomic epithelium at the sixth week. The proliferating cells migrate inwards and come to surround the medullary cells (Patten, '53; Arey, '46). Absence of the suprarenal is a common concomitant of unilateral renal agenesis. Collins ('32) reported absence of the homolateral suprarenal in 66 of his series of 581 cases, and the same anomaly was seen in 19 of our cases of unilateral agenesis-on the side of renal agenesis in one case with the mixed anomaly, and on the side opposite to the renal structures in one case of crossed renal ectopia. The ureter of the affected side was completely absent in 11 of the cases of unilateral agenesis, but in one there was a persistent partial development of the ureter to a length of 20 cm. from the bladder. It is usually accepted that the mode of origin

220

D. J. B. ASHLEY AND F. K. MOSTOFI

of crossed renal ectopia, in which there are two ureters draining either a double kidney or two separate kidneys on one side of the body, is due to the ureteric bud of one side "wandering" to the other (Potter, '52). In view of the finding of unilateral absence of the adrenal in association with this anomaly, it may be postulated that the cause of the deviation of the ureter from its side of origin is not random but is due to positive attraction by the metanephric blastema of the other side. A new hypothesis of the embryogenesis of the renal tract now becomes necessary. vVe suggest that the potentiality for renal differentiation rests in the structures of the nephrogenic ridge themselves. Both the pronephros and the mesonephros form their tubules and duct in response to organizers as yet unknown, and the stimulus for the outgrowth of the ureteric bud from the lower end of the mesonephric duct arises in the metanephric blastema at the lower end of the nephrogenic ridge. Full development of the kidney, of course, depends on the whole of this mechanism being intact. On the basis of this hypothesis, a new system of morphogenetic mechanisms for defects of renal development is put forward. We believe that all the combinations of anomalies of the renal tract are most easily explicable within the compass of this new system. Proposed classification of renal agenesis and dysgenesis: The new system classifies the anomalies of the kidney into six groups: 1) those in which the nephrogenic ridge fails to show any potentiality for differentiation as renal tissue, either because of its absence or because of qualitative changes; and 2) those in which the nephrogenic ridge fails to show full potentiality for renal differentiation after the formation of the proncphric and mesonephric ducts, the latter group being subdivided. 1) The nephrogenic ridge fails to show any potentiality for differentiation as renal tissue. 2) The nephrogenic ridge fails to show full potentiality for renal differentiation. a. The metanephric blastema fails to develop, and induction of the formation of a ureteric bud is absent. b. The stimulus for formation of the ureteric bud is present, but the ability of the lower end of the urogenital ridge to form renal tissue is deficient-

i. Completely. ii. Partly. c. The nephrogenic potentiality of the lowermost part of the urogenital ridge is retained, but the ureteric bud fails to develop, either because of the lack of specific induction from the ridge or because of field defects in the region of the bladder neck which lead to failure of this outgrowth. d. The stimulus for the formation of the ureteric bud is received from the opposite side of the body, the ureter is attracted to that side, and either a double renal pelvis or two renal pelves form the scaffold on which the nephrogenic tissues build the definitive kidney. The six different types of defect in the development of the kidney will cause defects in the anatomy of the urogenital system which may be predicted. The nature of these anomalies and their presence in the cases in this series will be discussed (table 7). Type 1 anomalies: Failure of the nephrogenic ridge to show any of its potentiality for organo-genesis will lead to the absence of all of the structures derived from this area; the pronephros, mesonephros, and the wolffian duct will not be formed; and the metanephros will not form the definitive kidney nor a renal rudiment. On the side of the anomaly, there will be no kidney and no ureter, the bladder will be deficient of one of the ureteric orifices; in the male the vas deferens will be absent, and there will be no seminal vesicle. The epididymis may, however, be present; this observation serves to cast doubt on the theory that the epididymis takes its origin only from the mesonephric tubules and suggests, rather, that it may be formed in part from the gonadal tissues proper. In a few cases, the area of embryonic deficiency may extend to the genital portion of the urogenital ridge so that the TABLE

Type

7. Proposed classification of renal defects Kidney

Ureter

Wolffian Duct ----

1 2a 2b-i 2b-ii 2c 2d

Absent Absent Absent Dysgenetic Dys genetic Absent

Absent Absent Present Present Absent Present on opposite side

Absent Present Present Present Present Present

RENAL AGENESIS AND DYSGENESIS

gonad, as well as the nephroi, may fail to be formed. If the total nephric failure were bilateral, the anatomical picture would be complicated by the failure of development of that part of the bladder which is formed from the lower ends of the wolffian ducts and the ureters, no trigone could be expected, and the absence of the normal stimulating force acting on the anterior part of the cloaca might, in some cases, give rise to a condition of hypoplasia or aplasia of the bladder. Type 2a anomalies: In this type of defect of nephrogenesis, the structures derived from the wolffian ducts will be present with the exception of the ureter; and because of the failure of development of the lower end of the nephric ridge, there will be no development of any renal tissue. In the male, the vesicles and vasa will be present. Type 2b-i anomalies: In this type of defect, the lower end of the nephric ridge is capable of inducing the formation of the ureter, either wholly or in part, but it is incapable of forming any renal tissue. The extent of development of the ureter is very variable. In some cases there is only a thin fibrous cord; in others the lowest part of the ureter is patent but has no connection with any structures higher up; and in still other cases the whole of the ureter, sometimes even with a renal pelvis, develops without the formation of any renal tissue. Defects of the wolffian ducts are not to be expected in this type of anomaly. Type 2b-ii anomalies: This variety of renal defect, in which the ureter is present up to the site of a rudimentary kidney, corresponds exactly to the renal aplasia of the earlier workers. No anomalies of the wolffian ducts are to be expected, and the adrenal glands will be found in their normal situation. The form of the ureter in this type of defect is very variable. A ureteric structure is present extending from the bladder to the rudimentary kidney; in some cases it is fully patent, in some there is a small lumen and the whole structure is markedly reduced in size, and in others it is represented only by a fibrous cord. The cause of this variation in ureteric size is unknown. By the general principle of positive evocation and induction in embryonic organogenesis, it may, perhaps, be postulated that the size of the ureter and its patency may be related to the amount of work it is called upon to do in intra-uterine life. It is

221

known that the fetal kidney excretes urine (Gersh, '37), although this is not a necessary physiological function, as live infants may be born without kidneys, and the high frequency of hypoplasia and fibrosis of the ureter in association with deficient renal structure may be due to the concomitant defect of fetal renal function. Type 2c anomalies: This type of defect, seen in 10 cases in the present series, is the most controversial. It has previously been reported only once, by Nation ('44), who recorded a series of 16 cases of dysgenesis of the kidney. In one of his cases there was complete absence of the renal pelvis and of the ureter, and in two others the upper ends of the ureters did not reach the kidneys. In this group it is suggested that the metanephrogenic blastema retains its potentiality for differentiation into renal substance, but that the inductive mechanism normally responsible for the formation of a ureteric bud is absent or that local field defects in the cloaca! region prevent the proper formation of the bladder and ureters. Four cases were seen in which one kidney was represented only by a small knot of tissue and in which no ureter was found even after careful search; in two of these cases there was no ureteric orifice on the corresponding side of the trigone, and in the other two no mention was made of the state of the bladder neck. There was 1 case in which only the lowermost 10 cm. of the ureter was present, and one in which the rudimentary kidney was removed, no ureter was seen, and there was no ureteric orifice on the homolateral side of the bladder. Three cases of bilateral renal dysgenesis were seen in which no ureters accompanied the small renal rudiments, and in two of these both ureteric orifices and the trigone were absent. In 2 cases of the mixed renal anomaly, no ureter was found on the side of the rudimentary kidney, and in neither of these was there a ureteric orifice on the affected side. This group of cases shows defects contrary to those which can be predicted from the present concept of renal embryology. It might be suggested that they could all be examples of inadequate autopsy technique. This somewhat autistic hypothesis must be rejected on two grounds. In the first place, the comparatively large number of these cases in a total series of 364 cases would indicate a low level of skill and integrity on the

222

D. J. B. ASHLEY AND F. K. MOSTOFI

part of the prosectors, who, in any event, would have been conditioned by their instruction in embryology to expect to find ureters in the presence of renal rudiments. Secondly, the observed absence of ureteric orifices in the bladders of five of these cases supports the concept that no ureters had developed in such anomalies. Another theory-that the ureters might have been reabsorbed completely after their formation-is also considered untenable because of the absence of ureteric orifices and because it is regarded as unlikely that structures which have already advanced to such a stage that they are capable of inducing formal organ differentiation would be resorbed. We would rather reaffirm our contention that the finding of these anomalies indicates that the present concept of the mechanism of formation of the definitive kidney must be replaced by the hypothesis that the inducing force comes from the metanephrogenic blastema and not from the ureteric bud. Type 2d anomalies: The anomaly in this group is the well-recognized one of crossed renal ectopy (Beer and Ferber, '37; Wilmer, '38). Both ureters are present, one from each side of the bladder, but they drain kidney tissue on one side of the body only. There may be one fused kidney on the one side, or there may be two separate kidneys, each draining into a separate ureter. In the present series of 8 cases, fusion of the kidneys was present in all. The etiology of this type of renal anomaly is the subject of controversy. Two principal theories are current: 1) that the ureteric bud on one side of the cloaca wanders over to the other side of the body and induces the tissue of the opposite metanephros to form additional kidney tissue (Potter, '52); and 2) that the ureteric bud induces the formation of a kidney in the metanephros on its own side but that the developing kidney is forced across the body by the pressure of the umbilical arteries (Wilmer, '38). Our hypothesis, involving a positive attraction by the metanephros for both ureters in the absence of metanephric structures on the other side, seems preferable to either of the current suggestions because it is consistent with the other anomalies which are seen in the renal tract, it retains the principle of positive attracting forces within the embryo, and it accounts for the transfer of the uretcric bud from one side of

TABLE

8. Distribution of anomalies within the proposed new classifi.cation * Type

1

I

2a

j

zb-i j zb-ii

I

2c

I

2d

I \~r

4 4

35

6

2

-·

j

2fb~r

Definite Male Right. Left. Bilateral. Female Right. Left. Bilateral.

14 24 2

2 2 2

6

3

12 7

2 1

-

49 27

-

-

1 2

-

-

-

1 1 2

3

-

2 2

-

-

8 11

5

12 1

-

6

-

l

-

Probable Male Right. Left. Bilateral. Female Right. Left. Bilateral.

I

I

I

-

-

6

16

-

-

-

-

7

-

-

-

-

-

I-

-

14 2

-

-

-

-

2

-

-

-

-

-

-

-

3 5

-

-

-

-

-

-

-

-

-

-

-

-·

I

-

1 I

-

I

* The cases of mixed anomaly are entered

under both types of anomaly. One case of bilateral renal agenesis is entered under type 2a and type 2b-i. the body to the other without passing close to the metanephric mass for which it is destined. Distribution of cases within the proposed new classification: The cases in this series have been reclassified according to the modified classification proposed here. Their distribution is shown in table 8. It was possible to make a definite decision as to type in the case of 83 males for whom the autopsy report gave details of the extent of development of the structures derived from the wolffian ducts. Of these, 18 fell in type 1; 38 into type 2a; 5 into type 2b-i; and 22 into type 2b-ii. A probable group designation could be given in the case of 13 males of type 2b-i (for whom the protocol did not mention the state of the vasa and vesicles, but in whom the ureters were present although there was no renal development) and in 32 cases which fell into type 2b-ii. In the latter cases, the ureter was present with a rudimentary kidney, but the state of the vasa and

RENAL AGENESIS A~D DYSGEN1'JSIS

vesicles was not reported, A further group of 111 males could be classified only as being either type 1 or type 2a, In these cases, there was complete absence of one or both kidneys and there was no ureteric development. In all but nine of these, it was noted that the ureteric orifice was absent on the affected side. In none was there a note of the state of the structures derived from the wolffian ducts, so that further categorization was impossible, In eight cases, differentiation between types 2a and 2b-i was not possible, as the ureter was simply recorded as absent and the condition of the bladder was not stated. In the case of the females in the series, the state of development of the wolffian duct system was, of course, not available as a guide to the type of anonrnly, Four fomales could be classified as type 2b-i, as there was some ureteric development, but no renal substance had been formed; and nine could be placed in group 2b-ii, as they :,;bowed ureteric development and rudimentary kidneys. Ten were eonsidercd probably to belong in type 1, as they had defects of development of the fallopian tubes and, in some instances, of the ovaries in association with the renal anomalieso Twent:v-one females were regarded as being either type l or type 2a, as all showed complete renal and ureteric agcnesis but had normal mtillerian ducts, In one case of bilateral absence of the kidneys, the ksion differed on the two sides, On one there was complete absence of the ureter, and no ureteric orifice was seen in the bladder; but on the other side, the ureter was partially present. In other words, the two sides corresponded to types 2a and 2b-i, respectively. In the case of the anomalies classed as mixed-those with renal agenesis on one side and renal dysgenesis on the other-the picture was more complicated. On the side of the renal dysgenesis, two showed the 2c type of anomaly and the remainder showed the 2b-ii type. On the other side the anomalies were variable. One of tht· cases with the 2c anomaly showed a type 1 anomaly on the other side, and the other had either a type 1 or a type 2a anomaly. Three of the cases with type 2b-i anomaly on one side had an anomaly of type l or of type 2a on the other, One had an anomaly of type 2a, one of type 2h-i, and in one instance the anomaly on the contralateral side was either of type 2a or of type 2b-i, This grouping of dissimilar anomalies within the range of variations

TABLE

9, Age distrilrn.tionfor 1mi/atera/ anmnolfr.s Age

Stillborn . Less than 1 mo, l mo. to 1 yr, . 1 to 20 yr,. 21 to 40 yL 41 to 60 yr. J\fore than 60 0

1 0

4 2

7 4 4

2

14

within one patient indicated the essential rcla tionship between the various types in the series, especially of those in group 2, The 18 cases classified as types 2r: and 2d have already been discussed in somr detaiL In a small remaining group, classification within the prepared framework was not because of the lack of data iu the reports. Age distribution within the uc11 classification: The age distribution of the ca.ses with unilateral anomalies which could be classified within the proposed schenrn is sho1,·n in table 9. Those who had bilateral anomaly nil died at an early age; 17 were stillborn, a.nd died in the neonatal period. There is little dif. fercnce in the age distributions of the different groups of unilateral defect, In all of the groups, a small proportion died in infancy and the mainder survived to die of other diserm· iu adult life. Associated anomalies of the {1(F)J?T/1'1n°1'17.IH'/J 8/)8° tem. Bladder anomalies: .Anomalies of the blacldt,r, apart from simple absence of the uretcric were infrequent, .Absence of the bladder wad noted in lO cases of bilateral rc-nal anomaJy, m}(i in 8 of these the urethra was also defoctive. In 14 other cases, again of bilateraJ anomalic,, the bladder was represented a vestigial fibrou,, structure either without a lumen or with onh a minute slit.. In all of these eases, the ureter,, wen, either absent or reprrsentecl n tltm fibrous band, and it is postulated that the forrnn tion of the bladder is dependent on the stinrnlns offered by the milffian duets joining the cloaca and the stimulus of the presence of fetal Ltri1w draining from the kidneys. Another which must be consiclerecl is that the agent in the production of the renal anomaly may also act on the blacldl'r primorclium or, as in the 0

224

D. J. B. ASHLEY AND F. K. MOSTOFI

anomalies of type 2c, that the primary anomaly is in this region. The possible nature of such a factor will be discussed later. Adrenal anomalies: The adrenal cortex, which may determine the form of the medulla, takes origin in the mesoderm of the upper end of the urogenital ridge. Absence of this organ indicates that the nephric dysgcnesis extends throughout the ridge, either as an initial phenomenon (type 1 defect), or as inability of the tissues of the ridge to show their potentiality of organogenesis (type 2b-i defect or type 2d defect). Eleven instances of the former type of abnormality were seen. In all of these the kidney, ureter, and adrenal were absent on one side, and in 10 of these it was noted that the corresponding ureteric orifice was also absent. One case was seen in which the ureter was present but no kidney tissue and no adrenal were seen on the affected side. This would be an extreme form of the type 2b-i defect in which the agent which caused the failure of the metanephric blastema to develop also inhibited the formation of the adrenal. In this connection, it must be noted that the earliest trace of adrenal gland formation is seen at about the sixth week of intra-uterine life (i.e., at the same time as the appearance of the ureteric bud from the lower end of the wolffian duct) and, therefore, that any agent acting on the metanephric blastema at this stage might also act on the adrenal blastema, which is only a short distance away; the whole embryo at this stage measures some 4 mm. in length. One case was seen in which there was absence of the adrenal on the side of the absent kidney in crossed renal ectopia. This case falls into type 2d. The mechanism suggested is that the nephrogenic ridge, including that part of it which was destined to produce the adrenal body, was subjected t.o some inhibitory agent after the mesonephric duct had developed but before the ureteric bud had been attracted to the lower end of the ridge. The contralateral metanephric blastema exerted sufficient evocation to cause the ureteric buds from both sides to develop and for one of the buds to cross the midline~again a very short distance~to form, with the normal bud, a double kidney. Gonadal anomalies: Absence of the testis or testes was seen in 10 of the males in the series, and in another 16 there was partial atrophy of the gonad. There was a similar defect of the

ovary in 7 cases, three of complete absence and four of hypoplasia. These are rare defects, and the association with renal aplasia must be more than a fortuitous occurrence. In all of these cases, there was a major interference with development; all fell into the groups in which there was no metanephric development (type 1 or 2a), and in most there was no ureter. In the cases of absence of the testis, the testicular defect was on the same side as the renal anomaly in four, and it was bilateral in one; one testis was absent in 3 cases of bilateral renal agenesis, and the heterolateral testis was absent in 2 instances of unilateral agenesis. In two of the cases with both testis and kidney absent on the same side, the vasadeferentia and seminal vesicles were also absent, and it may be suggestecl that there was in these cases a complete absence of development of the urogenital ridge on that side. In the other 2 cases of absence of both testis and kidney on the same side, there was no note in the autopsy protocol of the state of the vasa and vesicles, so that accurate grouping was impossible. The state of the wolffian ducts was also unknown in the cases with failure of development of one testis in the presence of bilateral renal agenesis, in the single case with no testes, and in the two cases with heterolateral testicular agenesis. Absence of the testis is a rare anomaly. Counseller, Nichols and Smith ('40) found a total of 54 cases in the literature, including 7 of their own; 11 of these were bilateral and the remaining 43 unilateral. Hepburn ('49) found another case of bilateral testicular agenesis from the literature and added one of his own, making the total at that time 13. Radasch ('08), in a survey of 225 cases of unilateral absence of the kidney culled from the literature, found 15 reports of absence of the homolateral testis, although Collins ('32) in his larger series found only four. This association of absence of the testis and absence of the kidney is adduced as evidence in favor of the hypothesis that the whole of the urogenital ridge and the structures derived from it have failed to develop, although in most instances the testes, which develop in a more mesial part of the ridge, are most frequently spared. The group showing atrophy of the testis on one or both sides is less clear-cut because of the frequency of atrophy of this organ as a result

RENAL AGENESIS AND DYSGENJ<;SlS

of disease or injury in extra-uterine life. However, in the majority of instances (seven of the eight with homolateral testicular atrophy) the lesion was associated with severe defect in the renal tract, and--by analogy with the findings in the female reproductive tract-it may be presumed that, in some cases at least, there is an embryological association between the two. The frequency of anomalies in the ovaries was higher than that in the testes, if the relative numbers of males and females are considered. Four females were seen in whmn the ovary was hypoplastic. In one of these, the histological appearance was identical with that seen in Turner's symlrome (Wilkins and Fleischman, '44). In one, the uterus and fallopian tubes were absent; in one, only the tube was absent; in one, the tube was hypoplastic; and in the other, the tube was in an abnormal situation behind the peritoneum of the posterior abdominal wall. All of these were associated with complete absence of the kidney and of the ureter on the side on which the ovary was hypoplastic. ]n the 3 cases of absence of the ovary, no ovarian tissue was found at all. The fallopian tube corresponding to the absent ovary was also absent, but in all three cases the uterus was present. These 3 cases were considered to fall within type 1, the kidney and ureter being completely absent in all cases. Anomalies of the uterus and fallopian tubes were seen in 10 cases in which both ovaries were present and normal. In two cases, both of bilateral renal agenesis, no miillerian development could be detected at all; and in one, also of bilateral renal anomaly, the uterus and tubes were extremely small. Unilateral failure of tubal development was seen in 2 cases, one of hypoplasia and one of complete absence of the tube. In five other cases there was failure of fusion of the lower ends of the miillerian ducts, with the formation of either a bicornate uterus or, in one case, uterus didelphys. This association of renal and female genital anomaly has been previously recorded (Radasch, '08; Collins, '32). Schumacker ('38) collected a series of 30 cases of the association of unicornate uterus and absence of the kidney and emphasized the nPcd for careful examination of the renal tract in cases of unilateral anomaly of the female genital system. As in the case of the male, it is suggested that the dcfeGts in the miillerian

system and in the ovaries are due to thee same embryological causes as have been for the anomalies of renal development. The mullerian ducts develop in dose anatornil:n.l relationship to the developing wolffian ductR in both sexes. It has even been suggested that the mullerian duct forms in the wall of the wolffian duct (Gruenwald, '41), and the hypothesis of defect in the whole field of the urogenital has been niade to account for this association. Further supporting evidence for this view absence of anomalies of the genital trad . either sex, where the renal lesion fell into one the groups in whic:h the presumed dcfed ,,as a lesser extent. External genitalia: Anomalous devdopnwnt of the external genitalia was an uncommon in the male. Five instances of hypospadia.s, all. penile, were seen, and in one of these tlwre grooving of the scrotum so that it resembled ill-formed vagina. In four of these cases, renal lesion fell either into type l or into the group in wLich it was not possible to deterrniDe whether the ksion was of type l or type None were seen in association with absence m severe atrophy of the testes. The date of fusiorc of the urethral folds-the third and foudh months of intra-uterine Iife-~makcs it unlikely that the inhibitory agent which acted on the renal primordium had persisted to affed the urethra, but rather suggests that there may have been a functional inadequacy of the gonad, which failed to induce complete formation of the ternal genitalia in this small proportion of case~. In the case of the female, defects in the ch vclopment of the external genitalia, as of the internal sex organs, were relatively more com· 111011. Five instances of anomalies of the cxtcnrnl genitalia were seen. In all of these there waR association with severe defect of the renal trnei. and also of the internal sex organs, and it nmy be postulated that the abnormal labia and occurred as a secondary phenomenon consequent upon the defects in the internal development of the patient. These five cases are discussed morn fully elsewhere (Ashley and Mostofi, '59). Etiology. Associated congenital anomalies: association of congenital defects in other of the body than the renal and genital a well-recognized concomitant of renal ""''.,'-''''"'° especially of bilateral lesions. Potter lw;, pointed out the almost constant association of

226

D. J. B. ASHLEY AND F. K. MOSTOFI

facies (Potter '46, '52) not being seen. The only other recorded instance of bilateral renal agenesis with normal facies is that of Levin ('52), who reported one such case. The incidence of other anomalies in the different groups of cases with unilateral renal anomaly was not strikingly different. Gastrointestinal abnormalities, especially of the rectum and sigmoid, were more common in the group with complete failure of the nephrogenic structures to develop (type 1) and those which could not be assigned either to 1 or 2a with certainty. Apart from this association, which we attribute to the closeness of the developing parts, the other more distant anomalies seemed to be of equal frequency in all groups. The specific anomalies followed a remarkably constant pattern. The most common were the cases of pulmonary defect, bilateral hypoplasia in bilateral renal defects and unilateral absence of

pulmonary hypoplasia and of a characteristic facial appearance with bilateral failure of renal development. Davidson and Ross ('54), in a large series collected from the literature, emphasized the frequency of anomalies of the lower limbs, in particular of talipes. The frequency of other anomalies is much lower in the collected series with unilateral defects. The anomalies seen have been tabulated twice, once using the older method of classification of these cases (table 10), and again using the new classification postulated here (table 11). The two tabulations confirm the view already expressed that other anomalies are much more common in bilateral than in unilateral renal anomaly. It is worthy of interest that in six of the cases of bilateral renal agenesis special note was made in the protocol that the lungs were of normal size, and in one of these a further note was made that the facies were normal, the typical "Potter" TABLE

10. Association of anomalies outside the genitourinary system with renal agenesis

and dysgenesis (Classification by former system) Unilateral Agenesis Unilateral Dys&eneOver 2 yr.

Under 2 yr.

SlS

Crossed Ectopia

Bilateral Agenesis

Bilateral Mixed Dysgenesis Anomaly

--No anomaly ........... .............. 177 Cardiovascular system Major ................. ............ 1 Minor .. .. . . . . . . . . . . . ............ 5 Central nervous system ........... Major ........... Respiratory tract Major ..... ........................ Gastrointestinal tract Major ....... ............. . . . . . . . . . Minor. . .. . . . .................. "Potter facies". ..... . . . . . . . . .. . . . . . . . . . . . . . . . ......... Upper limb. Lower limb. ................... . ......... 1 Ribs ..... . ........ Spine and pelvis. Diaphragmatic hernia ........ 1 Accessory spleen ........... 3 Cleft palate ... .......... Umbilical hernia ....... . ........ Cyclops ...... . . . . . . . . . . Micrognathos ........ . . . . . . . . . . . . . . . Cataracts ........ Cystic disease of kidney ............. * Size of the lungs not stated.

51 11

5

2

3

+ 5* 3

1

1

4

1

2

30

9

4

7 1 10 3

3

2

1 1

10 4

1 1

1 1

6

2

1 1

5

1

4

3*

19

4

2

1 1

1

1 2

1 2 2 2 1

1 1 1 1

2

REKAL AGENESIS AND DYSGENESIS

TABLE

Il. Association of anomalies ontside the genitourinary system with renal agenesi8 and dysyniesis* (Classification by the proposed system) Unilateral

No other anomaly .. Carcliovascular Major. Minor. Central nervous s:vstem. Respiratory tract. Gastrointestinal Major. Minor. Upper limb. Lower limb . Ribs .. Spine and pelvis. Diaphragmatic hernia. Accessory spleen. Cleft palate .. Cyclops. Micrognathos. Facies . Total cases.

1

1

1

l

1 1

2 4

Bilaleral

1 1

3

:1 1

1

2

1 4 2 2 1

2

1

2

1

7

24

2

l

7

1 l 1

1

:i

18

4

1 1

4

I

1 l

1 4

I I I

91

•)

u

2 2

I 2

21

6

37

8 !

:

I

1

I

521

~ ~-!-: I

1 6

41

* Cases with more than one type of renal anomaly have been coded with the more severe. In 56 cases the renal lesion could not be classified by the proposed system. These cases are omitle,d from this table. t Includes two cases in which the lungs were not measured, t Includes one case in which the lungs were not measured.

the lungs in three instances of unilateral renal agenesis. Anomalies of growth of the legs were the second most freqLicnt type of congenital defect in this series. Most of the lesions were simple clubfeet, the more bizarre types of lowerlimb fusion not being seen (Hinman, '40). :Vfajor anomalies of the mrdiovascular system, the nervous system, and the gastrointestinal tract \Yere seen in equal numbers. )'- particularly striking feature was the high incidence of lumbar meningomyelocele with the Arnold-Chiari malformation and internal hydrocephalus, which 1rns seen in a total of 12 instances, a very high frequency for such a comparati,-e]y rare anomaly. It is obvious that the association of other lesions with the absence of the kidneys and parts of the renal tract cannot be c'ntirely fortuitous. Davidson and Ross ('54) list the distribution of the anomalies seen in association \Yith renal agenesis and compare tlwm with those

seen in an otherwise unselected series of children with malformations. The striking featurps oi their material, as of ours, are the high of pulmonary and gastrointestinal malformation, of anomalies of the legs, and, in t.he Lmilateral group, the Arnolcl-Chiari malformation. The reason for this association is not difficult to find If it is recognized that many of the malformations seen are clue to factors deleterious fashion on the embryo during the stages of growth and development in the utcrn~, it will be seen that the effects of such causatin agents will act not only on the renal blash,nrn but also on any structure which is at a critical stage of development at the time that thE, metanephros and the urcteric bud arc together. It has already been mentioned that the metanephros and the ureteric bud a.re differ, entiating during the fifth a.ncl sixth weeks of intra-uterine life. This is a crucial period in the

228

D. J. B. ASHLEY AND F. K. MOSTOFI

life of the embryo, for at the same time many of the future organs are entering on stages of delicate adjustment on which the normal adult state of the body depends. The posterior end of the neural groove closes at the stage of 29 somites, the fourth week, and it is at this time that the limb buds appear; the lungs begin to form on the ends of the bronchial buds during the fifth week, the intestine undergoes rotation into the normal adult form in the sixth week, and it achieves communication with the outside by rupture of the anal membrane in the seventh week. At this time also, the form of the heart is established, the interventricular septum closes, and the septum secundum, which is to form the greater part of the interatrial septum, is laid down. The formation of the face and neck also takes place at this period (Arey, '46). It is not surprising, therefore, that multiple anomalies frequently arise in the series of structures which undergo these essential phases together. The major cardiac anomalies seen, defects of the interventricular septum and of the interatrial septum, may both be attributed to failure of the heart to show active growth of these essential parts at the time when they would normally be forming. Similarly, failure of the caudal end of the neural tu be to close in a normal manner will lead to the anchorage of the caudal end of the spinal cord at a much lower level than is normal. The cord, being relatively inextensible, will exert tension on the upper part of the central nervous system and cause it to prolapse into the upper part of the spinal canal, resulting in interference with the flow of cerebrospinal fluid in the subarachnoid space and hence in internal hydrocephalus-the Arnold-Chiari malformation. Pulmonary hypoplasia, gastrointestinal atresia (especially of the lower end of the gut), and anomalies of the face and limbs may also be attributed to failure of essential growth processes to occur at this same critical period. The tendency of the facial and pulmonary anomalies to occur with bilateral renal failure is possibly due to the wider extent of the inhibitory influences which cause bilateral anomalies, or it may possibly be that the production of bilateral anomalies requires some additional factor. Etiology: It was, at one time, customary to equate the terms "congenital" and "inherited," although certain exceptions such as congenital syphilis were recognized. This misconception is

no longer current, and a distinction is drawn between anomalies which are genetic in origin, i.e., due to the action of inherited genes, and others which have an external etiologic agent but which are manifest at birth. This action of external agents is shown in the observation of renal agenesis in one of a pair of uniovular human twins (Levin, '52). The effect of external factors on the fetus in utero has been studied extensively both in experimental material and in the human (Gruenwald, '56). Stockard ('20) showed that a variety of forms of treatment applied to developing embryos could cause a wide range of anomalies, and that the anomaly produced was more closely correlated to the time during development at which it was given than to the nature of the agent used. This rule-that the defect depends on the stage of development at which damage occurs rather than on the agent used to interfere with embryogenesis-has been tested and has been shown to be true (Wilson and Warkany, '48, '49; Duraiswami, '50), although there are, of course, exceptions such as masculinization of the external genitalia of the female fetus after the mother has been treated with androgenic steroids during pregnancy (Wilkins, Jones, Holman, and Stempfel, '58). In the human subject, in contradistinction to the experimental animal, it is often difficult to determine the external causative agent in congenital anomalies. The most noteworthy exception is the association between rubella occurring in the first trimester of pregnancy and defects of the heart and of hearing in the infant (Swan, '44). Faulty implantation of the ovum, with consequent defective nutrition of the fetus, has been suggested as a possible cause of defect (Mall, '17), and the toxic action of drugs such as quinine used in early pregnancy in an effort to induce abortion has also been implicated (Sylvester and Hughes, '54; Osmond, '55). It is probable, however, that the external agents causing a wide variety of congenital anomalies are less conspicuous even than rubella and will be determined only by epidemiological surveys of congenital anomaly similar to that conducted in Scotland (Anderson, Baird, and Thompson, '58). There appears to be no association with maternal age, parity, or with the complications of pregnancy (Allen, '51; Davidson and Ross, '54). In a few cases, genetic factors undoubtedly are

HIDNAL AGEc\l~SIS AND DYSGIDNESTS

responsible for renal anomalies. Madison ('34) reported a pair of siblings, both of whom had bilateral failure of renal development, and one case in this series had a sibling with a similar defect. In this case, the defect was classified as probably of type 2a. There was no anomaly of the; mlillerian duct system (the patient was female), and specific note was made of the nor· mal appearance of the face and of the normal lung weight. \Ve suggest that in this case there 1Yas a specific: genie abnormality which resulted in the inability of the nwtanephric blastema to produce renal tissue or to induce the outgrowth of the ureterie bud, but that the developmental potentiality of the remainder of the body was unimpaired. This finding is supported by the breeding experiments of Bagg ('29) and Danforth ('30) in the mouse and of Ratcliffe and King (' 41) in the rat. These workers wen, able to produce strains of rodents in which there was a high incidence of anomalies of the renal tract. These anomalies were inherited and were unaccompanied by defects elsewhere in the animal. It is probable that truly genetic bilateral defects in the growth of the kidney are rare. Data are not available cm the question of unilateral anomalies. This is a fielcl which will repay further family study. SUM'VIAHY

A seines of 364 cases of renal agenesis and clysgem,sis was studied in relation to the associated anomalies of the genitourirnuy system and to anomalies of other parts of the body. Eleven cases wne seen in which there was development of the kidney without a ureter being present. It is suggested that thc formation of the definitive kidney depends both on the presence of the LJreteriz; bud and on the existence of an adequate metanephrogenic blastenm, and that the urcteric bud devdops in response to induction from the developing metanephrns. It is proposed that these a.nomalirs should be reclassified, in the, light of our new concept of renal embryogenesis, into six groups, those in which~ 1) There, is eomplcte failure of differentiation of the nephrogenic ridge. 2) There is failure of development of the ncphrngenic riclgr after the formation of the pronephric and rnesonephric dnc:ts. a. There is failure of the metanephros with failure of inc!ucti011 of the ureteric bud.

b. Induction of the uretcric bud is present, bu!, the potentiality of the metancphro,, for forming renal tissue is deficient-i. Completely. ii. Partially. c. Induction of the uretrric bud is bu I the metanephros retains the ability tu form renal tissue. cl. There is failure of the nephrogenic one side, but the ureteric bud of that side induced by the contralateral and is attracted to the opposite sick of Urn body. The etiology of renal agenesis and r1vammo,a,~ is discussed. In many instances there are anornalirs of other parts of the body, and it r-;ng gestecl tbat all the concurrent defects are duc:o to extra .. embryonic factors which act on any pHxls of the embryo that a.ni nnclcrgoing critical stages in development at the time of action of the external stimulus. In a few cases it i~ rer,01z .. nizecl that gcnctie factors are responsible. REFERE'.\fCES

ALLEN, A. C.: The Kidney: Medical and Diseases. New York: Grune; & Stratton, ANnERsoN, vv. J. R.., BArnn, D. AND TH0.,1Ps01,: A. M.: Epidemiology of stillbirths ancl deaths due to congenital malformation. Ln.11. cet, 1: 1304-1:306, 19.58 ARJ,JY, L. B. · Developmental Philadelphia: W. B. Saunders AsHLEY, D. J.B. AND 1\.IosTOF'J, F. K.: female pseudohermaphrnditism in :issociatiun with renal a.genesis. In preparation. BAGU, H. J.: Hereditary al.monm,lities of Uw limbs, their origin and trnnsmission. If morphological study with special reference the etiology of club-feet, synda.clylism, dactylism, and congenital mnputation in descendants of x-rnyed mice. Am. J. AnnL. 43: 167-219, 1929.

B~JER, E. AND FERBER, W. L. F.: Crossed rnnnl ectopia (unilateral fused or elongated kidney) J. Urol., 38: 541-561, 19:>7. BELL, E.T.: Renal Diseases, 2nd eel. PhiJadclphin · Lea & Febiger, 1950. BoYD,Ji':, E. A.: Congenital absence, of the kidrH,y An interpretation based on a 10 mm. hnnmn embryo exhibiting unilateral. re11:1.l 2-?:Gnesis. Anat. Rec., 52: 325-349, rn:,2. BROWN, A. L.: An analysis of the developing 1m,Ln nephros in mouse embryos with almonnnJ kidneys. Am. J. Anal., 47: 117-171, rn::11. CAMPBELL, M. F. · Urnlogy. Phil:ulclphia: 'vV .ll Saunders Co., 1954, vol. I. CoLLl~S, D. C.: Congenital unilatcrnl renal n.grme sia.. Ann. Surg., 95: i15-726, 1D32. CouNSELLER, S.;r N1cH0Ls, f.). H.. A:\"D S}1r'_;_'H H. L.: Congenital absence o[ the testes.

,r.

1

J. Urol., 44: 237-241, 1940.

DANFORTH, C.H.: Dcvelopmenial n.nonmlies in ,1 special strnin of mice. Am . .J. Ann.t., 45: 27.5'· 287, J 930.

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DAVIDSON, W. M. AND Ross, G. I. M.: Bilateral absence of the kidneys and related congenital anomalies. J. Path. & Bact., 68: 459-474, 1954. DuRAISWAMI, P. K.: Insulin-induced skeletal abnormalities in developing chickens. Brit. Med. J., 2: 384-390, 1950. FORTUNE, C. H.: Pathological and clinical significance of congenital one-sided kidney defect with presentation of three new cases of agenesia and one of aplasia. Ann. Int. Med., 1: 377399, 1927. GERSH, I.: The correlation of structure and function in the developing mesonephros and metanephros. Contrib. Embryo!., Carnegie Inst., Washington, 26: 33-58, 1937. GRUENWALD, P.: The relation of the growing Miillerian duct to the Wolffian duct and its importance for the genesis of malformations. Anat. Rec., 81: 1-20, 1941. -: Environmental causes of abnormal embryonic development. Clin. Orthop., 8: 13-19, 1956. HEPBURN, R. H.: Anorchism. J. Urol., 62: 65-68, 1949. HINMAN, F. : Congenital bilateral absence of the kidneys. Surg., Gynec. & Obst., 71: 101-105, 1940. J osT, A.: Rec here he sur la differenciation sexuelle de l'embryon de lapin. III. Role des gonades fetales dans la differenciation sexuelle somatique. Arch. Anat. Mier. Morph. Exp., 36: 271315, 1947a. Experiences de decapitation de l'embryon de lapin. C.R. Acad. Sci., Paris, 225: 322-324, 1947b. LEVIN, H.: Bilateral renal agenesia. J. Urol., 67: 86-91, 1952. MADISSON, H.: Ueber das Fehlen beider Nieren. Zentralbl. allg. Path., 60: 1-8, 1934. MALL, F. B.: On the frequency of localized anomalies in human embryos and infants at birth. Am. J. Anat., 22: 49-72, 1917. NATION, E. F.: Renal aplasia: A study of 16 cases. J. Urol., 51: 579-586, 1944. OSMOND, R.: A report of three cases of bilateral renal agenesis. M. J. Australia, 1: 42-43, 1955. PATTEN, B. M.: Human Embryology, 2nd ed. New York: Blakiston Co., 1953. POTTER, E. L.: Facial characteristics of infants with bilateral renal agenesis. Am. J. Obst. & Gynec., 61: 885-888, 1946.

- : Pathology of the Fetus and the Newborn. Chicago: Year Book Publishers, 1952. RADASCH, H. E.: Congenital unilateral absence of the urogenital system and its relation to the development of the Wolffian and Miillerian ducts. Am. J.M. Sc., 136: 111-118, 1908. RATCLIFFE, H. L. AND KING, H. D.: Developmental abnormalities and spontaneous diseases found in rats of the mutant strain, Stub. Anat. Rec., 81: 283-305, 1941. SCHUMACKER, H. B.: Congenital anomalies of the genitalia associated with unilateral renal agenesis. Arch. Surg., 37: 586-602, 1938. STOCKARD, C. R.: Developmental rate and structural expression: An experimental study of twins, "double monsters" and single deformities and the interaction among embryonic organs during their origin and development. Am. J. Anat., 28: 115-277, 1921. SWAN, C.: A study of three infants dying from congenital defects following maternal rubella in the early stages of pregnancy. J. Path. & Bact., 66: 289-295, 1944. SYLVESTER, P. E. AND HUGHES, D.R.: Congenital absence of both kidneys. A report of four cases. Brit. Med. J., 1: 77-79, 1954.' WILKINS, L. AND FLEISCHMAN, W.: Ovarian agenesis: Pathology, associated clinical symptoms and the bearing on the theories of sex differentiation. J. Clin. Endocrinol., 4: 357-375, 1944. WILKINS, L., JONES, H. w., HOLMAN, G. H. AND STEMPFEL, R. S.: Masculinization of the female fetus associated with administration of oral and intramuscular progestins during gestation: N onadrenal female pseudohermaphrodism. J. Clin. Endocrinol., 18: 559585, 1958. WILMER, H. A.: Unilateral fused kidney: Report of 5 cases and review of the literature. J. Urol., 40: 551-571, 1938. WILSON, J. G. AND WARKANY, J.: Malformations in the genito-urinary tract induced by maternal vitamin A deficiency in the rat. Am. J. Anat., 83: 357-407, 1948. - : Aortic-arch and cardiac anomalies in the offspring of vitamin A deficient rats. Am. J. Anat., 86: 113-155, 1949.