The Influence of the Nerves on Kidney Function in Relation to the Problem of Renal Sympathectomy

THE INFLUENCE OF THE NERVES ON KIDNEY FUNCTION IN RELATION TO THE PROBLEM OF RENAL SYMPATHECTOMY L. F. MIJ:,LIKEN

AND

w.

G. KARR

From the Departments of Surgical Research, Biochemistry and Urology of the Graduate School of Medicine of the University of Pennsylvania and the Laboratory of Biochemistry of the Philadelphia General Hospital Received for publication October 31, 1924

Section of the sympathetic nerves (periarterial sympathectomy) has been practised in recent years with reputed good results in a variety of peripheral conditions, exhibiting sensory or circulatory derangement (1, 2, 3, 4, 5, 6, 7). This suggests the application of the operation to certain conditions of kidney pathology; and cases have already been reported in which denervation of the kidney has been practised for the relief of renal abnormalities, such as nephralgia and pain due to small nonmechanical hydronephroses (8, 9). The practicability of such a suggestion must depend upon the answer to the problem of the physiology of the renal nerves. It is our purpose to present a review of the literature on this subject with the results of certain experiments, and we planned with the idea of satisfying ourselves that at least no untoward functional disturbance would follow the loss of renal nerve supply. Many investigators, concerned with the physiology of urinary secretion, have partially or completely removed the kidney of the dog from its nerve supply and have compared, under various conditions, the function of the organ so treated with that of its normal companion. While the majority of these workers, using dissimilar methods, have arrived at practically the same conclusions, there are still enough dissenters to make the problems involved attractive. 1 THE JOURNAL OF UROLOGY, VOL. XIII, NO,

1

2

L. F. MILLIKEN AND W. G. KARR

The kidney is supplied with nerves principally by way of the renal plexus. This plexus arises from the semilunar ganglion through which it communicates with the greater and lesser splanchnics and the vagus (10). Usually it receives a branch direct from the lesser splanchnic and sometimes one from both the major splanchnic and the first lumbar ganglion (11). The splanchnic minimus, a small branch which is seldom found, runs from the last sympathetic ganglion to the renal plexus (12). The splanchnics, in turn, are formed mainly by fibers from the sixth to the twelfth dorsal nerves, although some fibers are found as high as the fourth dorsal and some as low as the third or fourth lumbar nerves (13). The renal plexus consists of nerve fibers and ganglia and is arranged in a network about the vessels of the renal pedicle. The nerve fibers enter the kidney with the renal vessels and follow them to their finest ramifications, small fibers being found in the smallest afferent and efferent vessels and even on the capillaries (10). Nerve fibrils have been described on and between the cells of the tubules and the capsule. The nerve fibers of the parenchyma of the kidney are usually non-medullated, while in the pelvis and the calyces they are frequently medullated. While the main nerve supply of the kidney is through the renal plexus, it is said that fine nerve filaments enter the kidney with the arteries which penetrate the fibrous fatty capsule, with an artery which enters between the kidney and the adrenal and with accessory (polar) vessels (11). The vagus also sometimes sends a branch direct to the kidney (10). It has not been shown that any nerves enter the kidney by way of t he ureter; it is said that the nerve supply to the upper portion of the ureter consists of small branches from the fibers of the kidney (14). BurtonOpitz has demonstrated that the innervation of the kidney is unilateral (15). FUNCTION OF THE RENAL NERVES

It may be well to give briefly the modern conception of the function of those nerves known to supply the kidney before presenting in some detail the more outstanding investigations on which these conceptions have been founded.

INFLUENCE OF NERVES ON KIDNEY FUNCTION

The principal function of the renal nerves is admittedly vasomotor. The splanchnic nerve conveys numerous vaso-constrictor and some vaso-dilator fibers to the kidney, but the vaso-constrictor action is much stronger than the vaso-dilator ; consequently, stimulation of the splanchnic trunk lessens the blood flow through the kidney and lessens the amount of urine secreted. On the other hand, depression or section of the splanchnic increases the amount of urine which assumes the characteristics seen in other forms of diuresis. There are no reasons for believing that the splanchnics contain any renal nerve fibers except the vaso-constrictors and vaso-dJ_lators (10). The vagus does not contain vaso-motor fibers for the kidney and there is no evidence that it affects the secretion of the urine in any way except indirectly by its influence on the heart (10). No secretory fibers to the kidney have been discovered (16). Asher and Pearce (17), in 1913, attempted to show that the vagus contains specific secretory fibers for the kidney, somewhat as the chorda tympani carries secretory fibers for the submaxillary gland. The great majority of investigators, with apparently the preponderant weight of evidence on their side, deny this. Howell (18) sums up the concensus of opinion when he says: "The majority of purely physiological experiments upon direct stimulation of the nerves going to the kidneys are adverse to the theory of secretory fibers, the marked effects obt ained in these experiments being all explicable by the changes produced in the blood flow through the kidneys." The evidence obtained in those experiments where the nerves going to the kidney have been sectioned or destroyed has been held by most observers to lead to the same conclusions. If the secretion of the urine depends upon specific secretory fibers to the kidney, sectioning of the renal plexus for pract ical purposes in the human would likely be attended by grave consequences. The "modern" theory of urinary secretion, set forth by Cushny (10, p . 44), ably supported and practically confirmed by many investigators, and especially by the notable work of A. N . Richards (19, 20) does not invoke the necessity or admit the existence of secretory nerves.

4

L. F. MILLIKEN AND W. G. KARR

Since the validity of this "modern" theory is sufficient refutation of the most likely theoretical objection to the denervation of the kidneys for practical purposes, it will be stated briefly. All th!e constituents of the blood plasma except the colloids pass by filtration through the glomeruli into the tubules. As this modified blood plasma passes through the tubules, there is reabsorption into the blood, in a constant concentration, of part of the water and of certain substances called threshold bodies. The remainder of the water and certain other substances called non-threshold bodies, which are not reabsorable by the tubules, are passed · on into the ureter and are excreted as urine. This theory of glomerular filtration and selective tubular absorption has been generally accepted, although certain doubts thrown upon it by the experimental work of Heidenhain (21) had never been cleared up until Richards' work was published. Richards' methods of observation have been recently employed by Bieter and Huschfelder (22) who have convincingly refuted the contention of Heidenhain that indigocarmin is excreted by the epithelium of the tubules. The reflex nervous mechanism of the kidney is not well understood, but it is believed that sensory efferent nerve fibers convey the impulses which induce the reflex. The reflex influences to which the renal function is subject are numerous. The application of cold to the skin or irritation of the sciatic nerve may decrease the secretion of urine. Irritation of the bladder or ureter by instruments or calculi may cause complete anuria. A stone in the kidney, a kinking or compression of the ureter and the ligature or the compression of the renal plexus by a tampon after nephrectomy may cause reflex anuria or oliguria on the other side through .a reflex spasm of the renal arteries. Again the pathology may be all on one side and the pain or other subjective symptoms entirely on the opposite side. In either case, we have the "reno-renal" or ,the crossed renal reflex. The pathway of these reflexes is believed to be in the splanchnic nerve, and the transference from one side to the other in the individual segments of the spinal cord (23). This subject has been ably reviewed by Fowler (24), and cases have been reported by Thomas and Sweet (25), Haines and Taylor (26) and others.

--------~--------

INFLUENCE OF NERVES ON Kl'DNEY FUNCTION REVIEW

OF

EXPERIMENTAL

WORK

ON

KIDNEY

5

DENERVATION

All subsequent investigation of vaso-motor phenomena has been based on the fundamental discovery of Claude Bernard, published in 1951, that section of the sympathetic nerve on one side would cause increased temperature on that side. BrownSequard proved, the following year, that the sympathetic nerves were true vaso-constrictors. Bernard, in 1859 (27), showed that section of a splanchnic on one side of a dog resulted in increased secretion of urine on that side. This has been confirmed by Eckard (28), Knoll (29), Klecki (30), Vogt (31), Grek (32), Rhode and Ellinger (33), Jungmann and Myer (34) and many later investigators. That innervation of the kidney is not essential to function compatible with life seems to have been established by many observers. In fact, it has been shown that excretion continues many months, perhaps indefinitely, after all connection with the central nervous system has been divided. Carrel and Guthrie (35) transplanted the kidneys of a dog into a bitch and removed the kidneys of the latter without fatal results. In this case the kidney carried on its function for many days without any guidance from the central nervous system. Lobenhoffer (36) claims that a transposed kidney is able to meet the ordinary demands of life. He was the first to study in a detailed way the function of the kidney after transposition. He severed the renal pedicle and transposed the kidney to the splenic vessels. Zaaijer (37) reports a dog living six years after its single kidney had been transposed to the iliac vessels, there-by removing it from any normal nerve influence. Dederer (38) transposed the left kidney of a dog to the neck and two weeks later did a right nephrectomy. The dog remained alive and well for more than four months after the operation. The transposed kidney excreted phenolsulphonephthalein rapidly, the transposed ureter functioned normally and there was a marked increase in the urine secreted by the kidney after the other was removed. Dederer also did a homotransplantation of a kidney and an ovary from one dog to another of the same litter (39) . The homotransplanted kidney func-

6

L. F. MILLIKEN AND W. G. KARR

tioned for twenty-six · days, until the dog died of distemper, although the dog had two kidneys of its own. Phenolsulphonephthalein injected intravenously appeared in the urine from the transplant in two minutes and forty seconds. Pathological examination showed that the organ reacted to the severe constitutional infection distemper, in a similar manner to that of the animal's own organs. There can be no question of this kidney having been entirely deprived of its nerve supply. Quinby (40) removed the kidney on one side in dogs, then reimplanted by anastamosing the severed renal vessels and the ureter. The unoperated kidney was removed in :five days to two weeks after the primary operation and the remaining or reimplanted kidney was found to be capable of maintaining life practically indi:finitely. Quinby claims that stripping the renal vessels of nerve :fibers gives unreliable results because a few of the nerve :fibers are actually within the vessels walls. He operated on 43 dogs, 16 of which survived in condition suitable for further experimentation. In his :first series, the dogs were anesthetized by paraldehyde in two days to three weeks after the primary operation; the ureters were brought out through the flanks and the urines were collected and compared. In this series, the denervated kidney showed increased function both for fluid and for salt, and this increase persisted for ten to fourteen days. It was noticed that the absence of nerves abolished the temporary inhibition of flow seen after handling the ureters. The normal side showed inhibition, while urine flowed from the ureter of the denervated kidney as soon as the ureter was opened. In a second series, nephrectomy was done on the normal side five days to two weeks after the preliminary operation. Elimination from the single denervated kidney in response to normal salt solution, lactose solution and phenolsulphonephthalein injected intravenously was then compared to that from a normal dog in which a single nephrectomy had been done. In each case the results were comparable and suggested the absence of secretory fibers to the kidneys. In a third series (41), he tested the response of the denervated kidney to hypertonic

----------

INFLUENCE OF NERVES ON KiDNEY FUNCTION

'/

solutions of sodium chloride, urea and caffein, given intravenously, and concluded that the reactions of the normal and the denervated kidney were practically identical for the same diuretics. Bellido of Barcelona (42) denervated one or both kidneys in the dog by cutting all nerve fibers running along the renal vessels. Denervation of one kidney resulted in moderate polyuria from that side. Injection of saline solution still further increased the excess of secretion from the denervated kidney over that from the Lormal kidney. He injected blood from a uremic animal, as a specific chemical stimulus, and found that the denervated kidney responded in the same way as the intact organ. If both kidneys were denervated, there was a polyuria lasting as long as two weeks, then gradual suppression and death m coma. Boeminghaus (43) denervated both kidneys at the same operation in 6 animals. The fibers of the renal plexus were torn away and the hilus and the kidney pedicle were painted with a concentrated solution of phenol as an additional safeguard, insuring destruction of all nerve elements. No observations concerning the function of the kidneys were made, but the dogs all lived until autopsied nine months later for the purpose of noting the condition of the ureters. Here the results were entirely different from those noted by Bellido. Marshall and Kolls (44) have been the most painstaking recent investigators studying the results of kidney denervation in relation to diuresis and urinary secretion. Their work has been described in five papers, published simultaneously. After the preliminary operation, their observations were made with the dog under paraldehyde anesthesia. In some cases the splanchnic nerve was sectioned, in others the renal plexus. The urine was collected from the ureters through small glass cannulae an hour before and an hour after giving various diuretics. They agree with Quinby that denervating a kidney causes incre~ed flow of urine on that side with a relative lowering but total increase of solids. They found that the changes in the urine on the operated side continued for months thereafter, differing

8

L. F. MILLIKEN AND W. G. KARR

from Quinby who found that they persisted for only ten to fourteen days. Marshall and Kolls assumed that the changes noted in the urine from the denervated kidney were caused solely by vasodilation with a corresponding increased blood flow through the kidney. They produced changes of an opposite nature by constriction of the renal artery. They found that where a denervated kidney was secreting three times as much urine as the normal kidney, paralyzing the splanchnic on the normal side reestablished the normal ratio. Varying results with chloride and sulphate diuresis after unilateral splanchnotomy ,confirmed their previous observations. They conclude that the burden of proof still rests with those who would assign a specific secretory-inhibitory action to the splanchnic nerve aside from the changes which it caused by being the chief vasomotor nerve to the kidney. Further confirmatory work has been reported by Marshall and Crane (45). We will mention briefly some of the work done by those who adhere to the theory of specific secretory nerves to the kidney without attempting to reproduce the convincing arguments made against their findings. These can be found in the literature already cited. The conclusions of Asher and Pearce, already mentioned, have since been denied by Pearce (46). Rohde and Ellinger (33) and Jost (47) have written papers in which they suggest that the splanchnic nerves carry fibers which act directly on secretory cells in the kidneys. Ellinger, again in 1921 (48), maintains that the splanchnic fibers accompanying the renal artery exert an inhibitory influence on the excretion of water and the solid constituents of the urine. He claims that the vagus and splanchnic affect water excretion in the same way, but that of the solid constituents in opposite ways. Koennecke (49) concludes from his experiments on dogs that a kidney deprived of its afferent nerves produces a urine which in itself appears normal in composition, but is deficient in saline content and amount as compared with the urine from the other kidney. He assumes that a kidney deprived of its nerves, and

INFLUENCE OF NERVES ON KIDNEY FUNCTION

9

acting purely automatically, suffices to maintain life under everyday conditions, but fails when greater demands are made upon it. "When the composition of the body fluids demands a rapid restoration of physiologic values by increased diuresis and elimination of salts, a kidney that has been cut off from nervous communication with the rest of the body cannot adapt itself to the increased demands." His findings concerning the amount of urine excreted by the denervated kidney are offset by those of Boeminghaus (43) whose paper appears in the same journal. This author states that he has always noted a definite increase in diuresis in the denervated kidney in dogs as compared with the intact organ. EXPERIMENTAL WORK

One of ust had already done some experimental work, as yet unpublished, in which, after denervating one kidney in the dog, we studied the function of the kidneys by cystoscopic methods such as are employed by urologists in determining unilateral kidney function. We have not found in the literature any record of this method having been previously employed in experimental work, except that done by Thomas in 1911 (50). In these experiments, some kidneys were denervated by section and reanastamosis of the renal vessels and some by stripping the renal vessels of all visible nerve fibers. Our post-operative observations were made without the use of an anesthetic, except in those cases where one was given to note its effect on kidney function. The relative function of the two kidneys was determined by chromoureteroscopy, using indigocarmin as described and employed by B. A. Thomas (51). The appearance time of the dye from each kidney was noted; also the color, whether light or dark bl~e; likewise the force, volume and frequency of the ejections. No quantitative estimations of the amount of urine or the percentage of dye from each kidney were made on account of the difficulty of making accurate unilateral collections. 1 Thesis for Master of Medical Science, L. F. Milliken, M.D., Department of Urology, Graduate School of Medicine, University of Pennsylvania.

10

L. F. MILLIKEN AND W. G. KARR

In all cases after denervation except one, the indigocarmin given intravenously appeared from the operated side in one-half to one and one-half minutes sooner than from the normal side. The jets from the operated side were more frequent (in some cases more than twice as often), they were projected farther across the field and the volume · of the stream was distinctly greater. The blue was not as deep as from the normal kidney. In the case noted as an exception, we found a sharp angulation of the vein at autopsy. When the dye was injected while the dog was still under the anesthetic immediately after the operation, the color appeared from the normal side usually in about six minutes, but was not seen to appear from the operated kidney in any case within fortyfive minutes. The dye usually appears from a normal unanesthetized dog in from three to four minutes. In the case of the dog with the angulated renal vein, the dye appeared from the normal kidney in three and one-half minutes and from the other side in six minutes. When the color ceased its appearance, the dog was etherized, the dye again injected and blue then appeared from the normal side in thirteen minutes and from the operated kidney again in six minutes. Hence it appears that the function of a normal kidney is inhibited by ether anesthesia, while that of a denervated kidney is not influenced. In 1 case, both ureteral orifices appeared at the same time in the field of the small cystoscope (No. 16 F.) that we were compelled to use, and the differences already mentioned could be easily noticed. This dog had been denervated by stripping away the renal plexus, and the difference in the function of the two kidneys was as apparent three months after the operation as it was a few days afterward. This case, as well as others, confirmed the utility of stripping the renal pedicle and gave additional evidence that the effects of denervation continue for some months at least. This dog was autopsied and the denervated kidney was found to be considerably larger than the other. On section, the cortex was found considerablythickened and there was corresponding increase in size of the other components. It showed every evidence, macroscopically, of

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

INFLUENCE OF NERVES ON KIDNEY FUNCTION

11

physiological hypertrophy and no evidence of infection or degeneration. This we consider corroborative evidence of increased blood supply to a denervated kidn'ey. The experiments of the writers were initiated by denervating both kidneys in a bitch at the same operation. This was accomplished by exposing both renal pedicles at the junction of the renal vessels with the aorta and vena cava, divesting the renal vessels of all surrounding tissue and then picking away all visible nerve fibers along the entire course of the vessels. We did not make any preliminary tests on this animal, but did the operation to check the results of Bellido whose anim_als had died in coma a few weeks after similar operations. Our dog made a normal recovery from the operation, did not at any time afterward exhibit any untoward symptoms, has since borne and suckled a litter of pups and is now alive and in exc,ellent condition seven months after the operation. One week after the operation, blood was taken from the jugular vein for the urea nitrogen determination. This was repeated for several consecutive weeks and at no time was the urea nitrogen content of the blood more than 14 mgm., per 100 cc. This is well within normal limits as compared with other dogs. Functional kidney tests were made at different times by injecting 2.5 cc. of 0.4 per cent indigocarmin solution after which the urine was collected during three periods of fifteen minutes each. The index of elimination was determined by dividing the percentage of dye eliminated during the first period by that of the third. Thomas and Birdsall (52) have shown that there is a close parallelism between the appearance time of the dye, the quantity eliminated, the "index of elimination" and the results of the various retention tests. Assuming 5.0 as a normal index, that being considered normal in the human where collections of urine are made at intervals of twenty minutes, we found that the kidneys of this dog had not been impaired in function so far as their ability to excrete dye was concerned. This dog was injected at different times with 100 cc. of normal salt solution, 100 cc. of 5 per cent sodium chloride solution and 35 cc. of 10 per cent sodium chloride solution. Indigo-

-

12

L. F. MILLIKEN AND W. G. KARR

carmin was injected at the same time with resultant indices of 6.12, 6.11 and 4.1, respectively. A series of experiments was performed to demonstrate if possible whether kidneys deprived of their nerve supply are able to meet the demands of unusual emergencies. Relatively large amounts of certain inorganic salts were given intravenously and a study made of the concentration of the salts in the blood stream as well as the amount and concentration in the urine. It was conceived that the disposition which the kidneys made of these salts before and after denervation might throw some light on their functional capacity. Female dogs were placed in metabolism cages and received 1 quart of milk on the day previous to the experiment. Water was given ad libitum. The next day after a fast of some twenty hours the dog was catheterized and the bladder irrigated. A sample of blood was drawn from the external jugular, indigocarmin was injected followed immediately by the hypertonic salt solution. The injection of the salt solution ordinarily required two to three minutes. The urine was collected every fifteen minutes after the injection of the dye for three periods. No water was given during these periods. At some time during this forty-five minutes a sample of blood was taken from the jugular. The dog was then placed in the metabolism cage and the urine again collected by catheterization five or six hours later and generally another blood sample taken at this time. The dog drank water freely when placed in the cage. The experiment was repeated after denervation of both kidneys. It is believed that these experiments in which an anesthetic is not required have a decided advantage over those performed otherwise. Marshall and Kolls (44) and Marshall and Crane (45) using somewhat smaller amounts of injected salt found a marked difference in the excretion of one denervated kidney when compared with \the normal kidney in the same animal. When nicotine tartrate was injected this difference disappeared and the normal kidney reacted in a similar manner to the one dener- . vated. The excess excretion of sodium chloride was not present and both kidneys responded as the normal kidney before the

TABLE 1 BLOOD

INJECTION

$ ':;;

.,,. ..,

s"

"',,0

" ,> 0

" """ ]·2 "'~

...... 9

>"

..,

-;;; U]

H

DYE

URINE

... A

'"Cl

...

"

$

0

-~ ':;;" b ·.3 "8 .g-a

"s 0" "''~ ,> P-< '"Cl"

" 0 0

B A

8

"' 0 0

$

§ i::

>. ..,,.

"" (l).s

:.:·s ""

.,"

...o..,,, f:g ., __ _,,

" s"

~~

..." .

.., 0

<

-~ 0

;;c:

""

."

.fr>

'"Cl

U]

0

H

per cent

per cent

""'

"

NaCl cc.

1/9

4/1

1/16

mM.*

Imoles I

min.

Before operation C 0.05010.0881 Nolmal After operation C 0. 05010. 091 Normal 1 Before D 0. 05010 . 088 Normal

1 4/15

4/23

5/14

4/17

5/12

After D 0. 05010. 093 Normal 1 2 Before E 0. 05010. 094 Normal 1 2 After E 0. 05010. 088 Normal 1 2 Before F 0. 05010. 093 Normal 1 2 After F 0.050 0.090 Normal 1 2

per liter

min.

cc.

moles per liter

moles

21 230

102 121 109

45 370

42 0.383 0.016 202 0.048

18 55

25.0 3.0

99 124

45 330

54 0.149 0. 008 264 0.026

9 29

41.4 3.4

21

96 114

45 360

40 0.221 0.009 300

10

28.0 10.0

38 36 380

99 120 111

45 370

62 0.209 0.013 0.067 270

14 72

22 360

106 126 109

45 355

118 0.230 0.027 0.081 420

30 86

34 365

102 126 110

45 360

117 0.223 0.026 0. 078 467

29 88

38 395

106 123 108

45 390

77 0.210 0.016 0. 070 447

17 75

38 420

105 122 107

45 420

105 0. 202 0.021 0.072

23 80

33.0 6.5

45 . 3 5.1

43.8 4.4

42.3 4.8

34.0 11 .8

Na2HPO,, NaH2PO,, pH 7.4

3/5

Before D 0.04010.033 Normal

1 2

5/22

After D 0. 03010. 024 Normal

1

29 360 40

0.94 45 7.7 1.1 360 0.93 5.3 13

36.9 5.1 80 0. 171 0.014 42 0.037 108 255 30.7 8.1

45

51 0.280 0.014

58

TABLE ! -Continued BLOOD

INJECTION

,.

,.

.£ "ii

" 0

"'....,, A

a3·~ >"

s"'

"A 0

:,

"o

>

2-2 .,-~

~

,; U1

DYE

URINE

H

:3"

"'

.£ "ii"

-~

ti

""' "" 0 0

'"O

'""" -~-~ QJ · ~

il-<

~,.

s"'

~

§ i::

>,

""' Cl>.S

~"' ,.., _,, "" ·.:·s

-<

~~ -;:; "' U1

0

moles

per cent

per oent

A

]

" ~

"'

"'

ti

~

"15

""s 0

" 0

0

~.9

"'~ '-"

~- ~

0~

5. ~ :,
""' "

'"O H

Na2HPO,, NaH~PO,, pH 7.4-Continued cc.

4/2

5/23

3/26

5/16

Imoles

ml\:1.*

min.

per liter

min.

Before E 0. 03010. 024 Normal 1.0 1 10 10.0 45 2 280 1. 6 275 After 0. 97 E 0. 04°1°.021 Normal 29 7.7 1 45 2 325 1.1 320 Before F 0. 04310. 032 Normal 0.77 1 35 8.5 45 270 After F 0.040 0.042 Normal 0.87 1 42 7.6 45 270

cc.

moles per liter

49 .7 6.3 62 0.173 0.011 182 0.022

45 91 36.8 5. 4

39 0.302 0.012 57 135 0.023 109 48.9 10.6 80 0.129 0.010 395 0.024

32 75 25.5

2. 6

115 0.175 0.020 48 605 0. 037 88

Na2SO, 2/27

Before C 0.04010.029

5/5

After C 0. 04010. 033

2/6

Before E 0.04010.033

5/19

After E 0. 04010. 028

2/13

Before F 0. 04010. 033

5/20

After F 0. 04010. 028

* mM = millimoles. 14

45 370

130 0. 128 0.017 57 237 0. 029 100

37.4 5.6

45 370

136 0.138 0.019 57 485 0.038 114

27. 0 3. 4

45 370

75 0.201 0.015 150 0. 031

46 94

37. 1 5.3

45 330

106 0.153 0.016 58 256 0.032 114

34.8 5.5

45 340

148 0.119 0.018 54 348 0.035 105

32. 0 5.5

45 340

111 0.154 0.017 61 316 0.030 106

40.3 9.2

INFLUENCE OF NERVES ON KIDNEY FUNCTION

15

nicotine injection. It is quite evident from the above experiment and the following data that excretion from the kidneys when both are denervated is quite different from the excretion of one denervated kidney with the other functioning normally. We may consider from the data given in table 1 the concentration of the salt in the blood stream, the amount of salt excreted in the urine in a given time, and the concentration of the salt in the urine. Similar data is compared before and after denervation. Retention of the salt in the body as shown by the concentration in the blood accompanied by delayed elimination in the urine is indicative of a diminished excretory power of the kidney. Examination of the data shows that practically all the injected salt is removed by the kidneys within a period of from five to seven hours. In dog C, NaCl is an exception. The denervated kidneys appear to be just as efficient as the normal kidneys. The concentrations of the salt in the blood stream are very similar before and after operation when taken at corresponding intervals after injection of the salt. Concerning the forty-five-minute period after the injection of the salt the data show an excretion of a more dilute urine after denervation than before. The average volume of the urine of the 4 dogs for this period and previous to the operation is 69 cc. with a concentration of sodium chloride of 0.261 mole per liter while after the operation the average volume is 85 cc. with a concentration of 0.196 mole per liter. However in the case of the phosphates the concentration is appreciably greater after the operation than before. The average concentration before is 0.158 mole per liter and after 0.252 mole per liter. The data on sulfate excretion is intermediate and not so conclusive, 1 dog having a decrease in concentration in the urine while the other 2 dogs' showed a slight increase. Although the dog was deprived of water during the forty-five-minute period the degree of diuresis is not as constant as might have been hoped. This is probably due to the degree of saturation of the tissues with water which is conceivably different in different animals and in the same animal at different times. The diuresis

t

!

16

L. F. MILLIKEN AND W. G. KARR

during the latter four to five hours when the dog was allowed water ad libitum showed much greater variation indicating no desire of the dog to take anywhere near a definite amount of water. No correction is made in the column of the per cent of the injected salt excreted in the urine for the amount of endogenous salt normally ercreted over that period of time, but as it is a fairly constant quantity it would in no manner affect the validity of conclusions drawn. DISCUSSION

Our experiments present additional evidence that a denervated kidney in a dog shows increased function over that of its fellow of the opposite side, and that this increased function may persist for several months. We have shown that denervation of both kidneys, to the extent of cutting away all visible fibers of the renal plexus, in experimental animals does not produce any untoward results and that these animals may afterward live in good health for an indefinite period; also that kidneys so treated are able to withstand exigencies more rigorous than are likely to occur under ordinary conditions of life. We cannot explain the results reported by Bellido, whose dogs died in coma a few weeks after the operation; but we believe that the work of Boeminghaus, who did double denervation of the kidneys at the same time in six instances and whose dogs lived until autopsied nine months later is reasonable substantiation of our results. It is believed that the denervation of one kidney disturbs the balance of function of the two organs in such a manner that the one which has been operated over functions considerably more than does either when both are denervated. Our collections of urine from the same animal before and after the double operation did not show any such excess of excretion after the operation as has been observed by most operators after denervation of one kidney. We had thought that the wide discrepancies noted in the amount of urine excreted at the same time by the normal and the operated kidney in the same dog might be

INFLUENCE OF NERVES ON KIDNEY FUNCTION

17

be partly accounted for by a double inhibition of function on the normal side. This could be caused by both the anesthetic and cannulation of the ureter where these had been used in making observations. We, however, noticed a considerable increase of function on the operated side in our cases where neither anesthesia or cannulation were used. All factors, particularly that of fluid intake, must be carefully controlled if consistent results are to be obtained in experimental studies on dogs. Animals given 350 cc. of water through the stomach tube forty minutes before functional kidney tests were done usually excreted more urine and a higher percentage of dye than they did after intravenous injection of any of the hypertonic solutions. Dogs kept from water for several hours prior to the tests excreted but little urine and considerably less dye. Before discussing the practicability of severing the renal nerve supply for the relief of pathological conditions in the human, it may be well to consider any theoretical or actual untoward results of the operation. The theoretical objection has been made that, if the majority of the motor fibers supplying the pelvis and the ureter pass through the renal plexus as Protopopow has stated (53), sectioning of the plexus might affect the peristalsis of the pelvis and the ureter in such a manner as to cause atonic conditions with secondary hydronephroses. Boeminghaus, who found no evidence of dilatation of either the pelvis or the ureter in any of his experimental cases nine months 'a fter section of the renal plexus, seems to have disposed of this objection. It may be suggested that cutting of the renal plexus, which may carry true secretory fibers to the kidney, might interfere with the production of some vital internal secretion. Granting the existence of such a secretion, any objection based on this presumption can hardly be tenable so long as the existence of secretory nerves to the kidney cannot be proved. Interference with the production of any vital secretion can hardly be considered in the absence of untoward symptoms after the operation.

18

L. F. MILLIKEN AND W. G. KARR

Adami (54) has stated that a single remaining hypertrophied kidney is lacking in reserve power and very liable- to disease. If this is true of an hypertrophied kidney, it might reasonably be true of an overfunctioning denervated kidney. We consider this the only theoretical objection not easily refuted, but -it is one which has not yet been proved. Koennecke's objeotion, that a denervated kidney cannot take care of unusual emergencies, is not supported by experimental evidence.

Theoretical considerations Several cases have been reported during the past year in which renal sympathectomy has been done for the relief of nephralgia and small painful hydronephroses. Papin and Ambard (8) have reported 6 such cases and Legueu and Flandrin (9) have reported 8 more. In most of these cases, the relief from pain was complete a few days after the operation. Their clinical experience thus sustains the physiologic and surgical bases and the practical utility of tearing out the nerves in the pedicle of the kidney. Deductions made from the results of experimental work and the known physiology of the renal nerves justify us, we believe, in suggesting the operation for the relief of other abnormal renal conditions. A. Theoretically, it appears the logical procedure in reflex anuria. N euwirt (23) has reported 1 case in which he treated reflex ahuria due to stone by anesthetizing the splanchnic nerves on each side with 30 cc. of 1 per cent novocaine-adrenalin solution. Fifteen minutes afterwards the severe colicky pain had entirely subsided and kidney function had been reestablished. Both sides were anesthetized on account of uncertainty in the diagnosis. Theoretically, unilateral anesthesia would have been sufficient. Since reflex anuria and oliguria are produced by spasm of the renal vessels occasioned by reflex stimulation of the vaso-constrictors, and since there impulses are carried only by the splanchnics, inhibition must cease and function must be restored when

INFLUENCE OF NERVES ON KIDNEY FUNCTION

19

these nerves are anesthetized or sectioned. The same must happen when the renal plexus is severed, and tnis procedure would probably be more convenient for most operators than would anesthetization of the splanchnics. Either method would appear preferable to decapsulation of the kidney which has been so often employed. B. Papin and Ambard, performed the operation for the relief of pain in the two conditions already mentioned. They not only stripped away the nerves of the renal plexus, but they broke up all the attachments of the kidney and ureter, decapsulated the kidney and then did a nephropexy. Theoretically, the same relief from pain might have been secured by resecting the renal plexus without decapsulation of the kidney and breaking up of its normal supports with subsequent nephropexy. These small non-mechanical hydronephroses are supposed to be the result of destruction by chronic disease of the equilibrium of nerve impulses going to the kidney, in consequence of which inhibitory influences gain the upper hand (43). If that is true, we may have in the ureter a condition analogous to that of spastic paraplegia which has been so successfully treated recently by section of the sympathetic nerves (55). If we accept this hypothesis, we might just as reasonably expect a cure from the operation in this type of hydronephrosis as to expect rel~e;f of pain. It is possible that those who have used this method of treatment in these cases may have overlooked that which may prove to be the vital feature of the operation. C. It has been observed that where one kidney has been removed on account of advanced tuberculosis the remaining kidney, although it too may be infected, apparently heals in and performs the work of both indefinitely (56). The healing in or arrest of the disease in the single kidney is supposed to be due to the increased blood supply incident to increased function. Assuming this hypothesis to be correct, it is p'qssible that denervation of a kidney might act favorably by increasing its blood supply with ultimate arrest of tuberculous infection, especially in those cases where the infection is recent or limited.

20

L. F. MILLIKEN AND W. G. KARR

Cases have been reported in which tuberculosis of the extremi-ties, such as joint and bone tuberculosis, have been arrested by periarterial sympathectomy (57). Theoretically, we would expect more favorable results from such an operation in a vascular organ like the kidney than we would in bone. We do not expect surgeons to be led away, without good reason, from the time honored practice of removing at once the infected kidney when it can be proved that the other is not similarly infected; but we believe that there is sound theoretical justification for giving this method of treatment a trial in selected cases. It would in n'o way preclude a later removal of the kidney if necessary. As the early signs and symptoms of tuberculosis are better understood, and as it becomes possible to make early diagnoses of this condition with greater frequency, this form of treatment might be the means of saving some kidneys that are now sacrificed. D. When the nerves of the renal plexus are stripped away, a condition of over function is produced in the kidney comparable to that of any form of ordinary diuresis; i.e., there is increased excretion of urine which is of lower specific gravity. This suggests renal sympathectomy for the prevention of the reformation of renal calculi in cases where n'ephrolithotomy has been done. Theoretically, it- would cause a better flushing of the kidney by a more dilute urine for at least several months afterward. Denervation could be done while the kidney is exposed for removal of the calculi, and without adding materially to the hazard of the operation. E. Decapsulation of the kidney has long been practiced as a last resort in certain forms of nephritis. Theoretically, section of the renal nerves would give as good or better results than d'ecapsulation and it would be a less mutilating procedure. Boeminghaus (43) is of the opinion that the effect of decapsulation is similar to that of denervation. He says: "Theoretically, decapsulation is not well founded since the expected permanent relief of pressure or improved· vascularization is not obtained." It seems likely that subsequent cicatrization would soon nullify any good effect produced by decapsulation.

INFLUENCE OF NERVES ON KlDNEY FUNCTION

21

'This view seems so reasonable that denervation instead of decapsulation should at least be given a trial. In certain cases, perhaps, the two methods might be advantageously combined.

The operation We believe that the best approach for this operation is through a median abdom[nal or a longitudinal rectus incision. By the transperitoneal route, the renal vessels can be exposed at their junction with the vena cava and the aorta. They can then be denuded outward toward the kidney of all investing tissue, and sufficient exposure can thus be obtained for stripping away all the fibers of the renal plexus along the entire course of the vessels. The stripping away of all visible nerve fibers is suffident denervation for any practical purpose. By this method, the natural supports of the kidney are left intact, mauling of the organ is avoided and the formation of extensive perirenal adhesions is prevented. This prevention of adhesions is very important, especially if need should later arise for surgical approach to the kidney by way of a lumbar incision. The operation can be done more quickly and with less difficulty than if done through a lumbar incision, and in case the renal vein is torn, as sometimes happens (8), the damage can be more conveniently repaired. Any theoretical objections to opening the peritoneum are more than offset by the obvious technical advantages gained by this method. Quinby says: "The approach to the kidney across the peritoneal cavity permits immediate attack on the vessels of the organ if such should be deemed necessary. The renal vascular pedicle is easily reached through the retro-peritoneum by transabdominal approach" (58). CONCLUSION

Renal sympathectomy, in experimental animals, has been shown to produce certain definite changes in kidney function which continues for an indefinite period. No untoward results follow the operation even when both kidneys are deprived of their nerve supply at the same time. Periarterial sympa-

22

L. F. MILLIKEN AND W. G. KARR

thectomy has given good results in certain peripheral sensory and circulatory abnormalities, and renal sympathectomy is theoretically practicable and is indicated in analogous kidney conditions. The changes in kidney function produced by section of the renal sympathetics would seem to be of a nature valuable in correcting the dysfunction in those condit ions of kidney pathology mentioned in this paper; and since there appear to be no contraindications, the operation would seem to be entirely justifiable and, in many cases, preferable to any other method of operative procedure. REFERENCES (1) (2) (3) (4)

LERICHE, R: Presse med., 1922, xxx, 1105. MULLER, G. P .: Ann. Surg., 1923, lxxvii, 641. BRUNING, F., AND FORSTER, E. : Zentralbl. f. Chir., 1922, xlix, 913. HALSTEAD, A. E., AND CHRISTOPHER, F.: Jour. Amer. Med. Assoc., 1923, lxxx, 173. (5) SHERWOOD, W. A.: Ann. Surg., 1923, lxxviii, 321. (6) GuNDERMANN: Beit. z. klin. Chir., 1923, cxxix, 231, (7) KuMMELL, H ., JR.: Zentralbl. f. Chir., 1922, 1, 1434. (8) PAPIN, E., AND AMBARD, L .: Arch. Franco-Belges de Chir., 1923, xxvi, 615. (9) L_EGUEU, F., AND FLANDRIN, P. : P resse med., 1923, xxxi, 741. (10) CusHNY, A. R . : The Secretion of the Urine, 1917, 8. (11) PAPIN, E., AND AMBARD, L.: Jour. Urol., 1924, xi, 340. (12) PAWLENKO, W. A.: Verhandl d . Russ. Chir. Pirogoff- Ges., 1921. (13) BRADFORD: Jour. Physiol., 1889, x, 358. (14) LATARJET, A., AND BERTRAND, P. : Lyon Chir., 1923, xiii, 31. (15) BuRTON-OPITz: Amer. Jour. P hysiol. , 1916, xl, 437. (16) WHITE AND MARTIN: Genito-Urinary Surgery and Venereal Diseases, Philadelphia , 1920, xii, 589. (17) ASHER AND PEARCE : Zeitschr. f. Biol., 1913, lxiii, 83. (18) HOWELL, w. H.: A Text Book of Physiology, 1918, 840. (19) RICHARDS AND SCHMIDT: Amer. Jour. Physiol., 1922, lix, 489. (20) RICHARDS, A. N.: Amer. Jour. Med. Sci., 1922, clxiii, 1. (21) HEIDENHAIN: Pfluger's Arch. f . d. ges. Physiol., 1874, ix, 1. (22) BEITER, R. N., AND HrnscHFELDER, A. D. : Amer. Jour. Physiol. , 1924, lxviii, 326. (23) N EUWIRT, K: Ztschr. f. U rol. Chir., 1922, xi, 75. (24) FowLER: Surg., Gynecol. and Obstet., 1916, xxii, 454. (25) THOMAS, B . A., AND SWEET, J . E.: Jour. Urol. , 1922, viii, 131. (26) HAINES, W. H., AND TAYLOR, K . P.A.: New York Med. Jour., 1921, cxiii, no. 1, 197. (27) BERNARD, CLAUDE: Lecons sur les proprietes physiologiques des liqiudes de l'organisme, 1859.

INFLUENCE OF NERVES ON KIDNEY FUNCTION

<28) ,(29) ,(30) ·(31) ·( 32) -(33) (34) •(35) (36) ·(37) (38) •(39) ·(40) -(41) (42) •(43) (44) ·(45) •(46) •(47) (48) (49) (50) (51) (52) (53) (54) (55) (56) (57) •,(58)

23

EcKHARD: Beitr. z. Anat. u. Physiol., 1869, iv, 153. KNOLL: Beitr. z. Anat. u. Physiol., 1872, vi, 41. KLECKI : Arch. f. Exper. Path. u. Pharm., 1879, xxxix, 173. VoGT: Arch . f . Anat . u. Physiol., 1898, 399. GREK: Arch. f. Exper. Path. u. Pharm., 1912, lxviii, 305. ROHDE AND ELLINGER : Zentralbl. f. Physiol., 1913, xxvii, 12. JuNGMANN AND MEYER: Arch. f. Exper. Path. u. Pharm., 1913, lxxiii, 49. CARREL AND GuTHRIE : Science, 1906, xxiii, 394. LOBENHOFFER : Mitt. a. d. Grenzgeb. d. Med. u . Chir. , 1913, xxvi, 197. ZAAIJER, J. H . : Beit. g. klin. Chir., 1914, xciii. DEDERER, CARLETON, JR. : Jour. Amer. Med. Assoc., 1918, lxx, 6. DEDERER, CARLETON, JR.: Surg., Gynecol. and Obstet., 1920, xxxi, 45. QUINBY, W. C .: Jour. Exper. Med., 1916, xxiii, 535. QUINBY, W. C . : Amer. Jour. Physiol., 1917, xiii, 593. BELLIDO, J.M . : Treb. de la soc. biol., Barcelona, 1917, 304. BoEMINGHAUS, HANS: Arch . f. klin. Chir., 1923, cxxvi, 74. MARSHALL AND KoLLs: Amer. Jour. Physiol., 1919-1920, xlix, 302-342. MARSHALL AND CRANE: Amer. Jour. Physiol., 1922, lxii, 330-340. PEARCE AND CARTER: Amer. Jour. Physiol., 1915, xxxviii, 350. JosT: Zeitschr. f. Biol., 1914, lxiv, 441. E LLINGER, P. : Arch. f. Exper. Path. u. Phann ., 1921, xc, 77. K oENNECKE : Arch. f. klin. Chir., Berlin, 1923, cxxvi, 63 . THOMAS, B . A.: Amer. Jour. Med. Sci., 1911, cxlii, 376. THOMAS, B. A. : Surg., Gynecol. and Obstet., 1911, xii, 345 . THOMAS, B. A., AND BIRDSALL, J . C.: Jour. Amer. Med. Assoc., 1917, lxix, 1747. PROTOPOPOW: Arch. f. ldin . Chir., Berlin, 1923, cxxvi, 74. ADAMI AND NICHOLS: Principles of Pathology, 1909, ii, 764. RoYLE, R. N.: Med. Jour . Australia, January 26, 1924. KuMMELL, HERMANN: Ztschr. f. Urol., 1920, 18. LAWEN, A.: Munchen med. Wchnschr., 1924, lxxi, 107, p. 3. QuINBY, W. C.: Jour. Urol., 1921, vi, 135.