THE EFFECT OF RENAL DENERVATION ON PATIENTS SUFFERING FROM NEPHRITIS
Irvine H. Page, George J. Heuer
J Clin Invest. 1935;14(4):443-458. https://doi.org/10.1172/JCI100695.
Research Article
Find the latest version: https://jci.me/100695/pdf THE EFFECT OF RENAL DENERVATION ON PATIENTS SUFFERING FROM NEPHRITIS 1 BY IRVINE H. PAGE AND GEORGE J. HEUER (Fromn the Hospital of The Rockefeller Institutte for Medical Rcsearch, and The Suirgical Departmentt of the Newr York Hospital and Cornell Medical College, New York City) (Received for publication February 27, 1935) Jaboulay (1) appears to have been the first to numerous within the plexus are not found in the perform the operation of periarterial neurectomy renal parenchyma. in man. The procedure, however, did not achieve Smirnow (9) observed that the nerves follow popularity until after the appearance of a series the blood vessels into the renal tissue even to the of papers by Leriche and his associates (2, 3). smaller capillaries. Motor nerve endings were The effect on patients suffering from peripheral seen in the smooth muscle of the vessels, as well vascular disease has been especially extensively in- as small nerve fibers in the capillary tuft of the vestigated. Denervation of the kidneys more re- glomeruli, the glomerular membrane and in the cently has been performed on patients suffering tubules. Sensory nerve endings occurred in the from nephralgia and hydronephrosis, success be- smooth muscle of the pelvis and in the connective ing achieved in the relief of pain. tissue of the adventitia and media of most renal vessels and the capsules. Secretory nerves to the ANATO M ICAL kidneys have never been convincingly demon- strated (Cushny (10) ). The renal nervre supply is derived mainly from the celiac ganglia with small branches from the plexuses around the adrenal gland and the aorta. PH YSIOLOGICAL Usually one branch comes from the splanchnic Section of the splanchnic nerves in animals was nerves direct. Through the celiac ganglion the shown by Claude Bernard (11) to be followed renal nerves are brought into connection with the by increased excretion of urine more dilute than splanchnic nerves and with the vagus. The vagus normal. This observation has been confirmed nerve also sometimes- sends a direct branch to the many times (Eckhard (12), Klecki (13) Grek kidneys. A few branches are received from the (14), Rohde and Ellinger (15), Asher and superior mesenteric ganglion. Pearce (16), Jungmann and Meyer (17)). It It has long been recognized that the splanchnic also increases markedly the elimination of chlo- nerves form the chief vasomotor supply of the rides and carbonates and to a less extent that of kidneys. Bradford (4) found that stimulation of urea, phosphates and sulfates. Elimination of the anterior roots of the cord from the sixth creatinine, ammonia and phenolsulfonphthalein is thoracic to the second lumbar segment caused the unchanged according to Marshall and Crane (18). kidneys to constrict. Of these roots the tenth to Section of the splanchnic nerves in frogs causes twelfth dorsal were most effective. Vasodilator more glomeruli to fill with blood than in the con- fibers were also present but were weak in com- trol kidney (Bieter (19)). Should polyuria, in- parison with the constrictors. creased blood flow and increased excretion of salt Langley and Anderson (5), Jost (6), and Hirt and urea, occur following denervation of the kid- (7) have clearly demonstrated fibers coursing neys in patients, it would be of benefit. from the third, fourth, and fifth lumbar ganglia Burton-Opitz and Lucas (20) showed that the to join the renal plexus. Most of the nerves are vasoconstriction following stimulation of the non-medullated, but some in the plexus are my- splanchnic nerves or renal plexus occurs only elinated (Renner (8)). Ganglion cells which are on the side stimulated. Complete section of the renal nerves in animals was probably first per- 1 Delivered at the International Medical Assembly, In- terstate Postgraduate Medical Association of North formed by Carrel and Guthrie (21, 22). They America, Philadelphia, November 8, 1934. were able to transplant both kidneys from one 443 444 IRVINE H. PAGE AND GEORGE J. HEUER
a,i'c8'ebreifro.:V MI
I;
Ii;p.dg,--" 1 .~~~~
t'
''''.:(l(3 :~~~~~~~~'' 2~~~~~~~~~~~""e,i
1'FIG. RENAL NTERVES IN MAN.
From A. Hirt, Ztschr. f. Anat. u... EntwichunIgI Gesch., 1924, 73, 621.
dog to another after having removed both kidneys urine. Administration of pituitrin reduced the from the latter. Except for some protein, the increased output to normal. Bayliss and Fee urine excreted was normal. This work was con- (29) found that p)erfusing inniervated kidneys firmed by Dederer (23, 224), Ibuka (25), and witlh heart-lung p)relparations, unlike isolated per- Holloway (26), who further showed that homeo- fused kidneys, did not excrete large amounts of transplants function adequatelv for some time. hvpl)otonic urine until (lenervation was effected. Lobenhoffer (27) found that transi)lantedl kid- Renal (lenervatioln, just as slplanchnic section in neys remain histologically normal at least for a norm-lal (logs, results in (liuresis which may l)ersist few weeks,nor was there any difference in trans- for mlonths (Rohdle and Ellinger (15), Stierlin plantedI andenormal kidneys in their ability to ex- a(ld Verriotis (30), Caldwell, M\arx, and Rown- crete water and sodium chloride. Diuresis in- tree (31)), or not more than two weeks (Quinbv duceI whaydremia showed that vascular efficiency (32)). The total anmount of water, chloridles was laintainied. alnl urea eliminated was greater on the denervate(I Animals in which total hypopahysectonm fol- si(le, and( with little change in the amount of cre- lowed 1w (lecerebration had been performedi (lid atininie and phenolsulfonl)hthalein (Marshall and not exhibit increased flow of urine or any moarked Kolls (33), Milliken and Karr (34), Kusakari change in the output of chloride (Fee (28)in- (35)). Denervation of the kidnevs, however, resulted in Hiecht's exl)eriment (36), in which oil was in- the pnrouction of large amhounts of hypotonic jecte(l into the ao)rta after tying the vessel distal RENAL DENERVATION IN NEPHRITIS 445 to the renal arteries, showed that more oil entered greatly reduced and the excretion became con- the vessels of the denervated than the normal kid- tinuous (Milles and Nedzel (44)). It is possible ney. MIilles, Mfiller and Petersen (37) also that intermittency of excretion was due to periodic found by x-ray examination of injected kidneys activity of the glomeruli (Richards and Schmidt that denervation caused chronic vasodilatation. (45) ). Quinby (32) tested the response of denervated Kidneys of dogs following injection of colon kidneys to intravenous injection of hypertonic so- bacilli, were not apparently injured for a period lutions of sodium chloride, urea and caffeine, and of about 30 minutes but, with the onset of chills, found that the reactions were practically identical albumin, red blood cells and bacteria appeared in with those of normal kidneys. the urine (Mufller, Petersen and Rieder (46)). Rhoads, Van Slyke, Hiller, and Alving (38) If one kidney had been denervated, it continued have shown that infiltration with novocaine or to excrete normal urine after the injection of bac- section of the renal nerves in dogs was without teria in spite of chills. Moriconi (47) was un- consistent effect on either the excretory efficiency able to prevent the appearance of suppurative of the kidney, as measured by the urea clearance, nephritis in dogs by decapsulation and denervation. or on the renal blood flow. There appeared, It has been a favored theory that arterial hyper- nevertheless, to be a possibility that the renai tension in nephritis is due to nervous reflexes blood flow, and with it the function, might be in- originating in the kidnevs. Experiments per- creased in nephritic patients by denervation. formed on dogs bv Page (48), in which renal Mliuller and Petersen (39) observed that de- hypertension had been produced by constricting nervation prevented infection of kidneys by colon the renal artery (Goldblatt, Lynch, Hanzal and bacilli infused intravenously. X-ray photographs Summerville (49) ), did not support this view. taken after injection of an opaque medium showed He showed that hypertension resulted even when that dilatation of the larger arteries had occurred the nerve supply to the kidneys was severed. It on the denervated side. Chilling animals caused was considered important to ascertain in patients constriction of the renal vessels in the innervated whether the renal nerves were concerned in the but not in the denervated kidneys. (Milles, Miil- genesis of nephritic hypertension. ler, and Petersen (40) ). If the chilling was re- peated daily, morbid changes occurred in the vas- PREVIOUS CLINICAL DATA cular bed of normal kidneys, conversely dener- Temporary partial denervation of the kidneys vated kidneys remained unaltered. Clinical ob- been by means of in- of the skin as an has attempted paravertebral servation has implicated chilling of local anesthetics. Wiedhopf (50) of and jections important cause in the initiation nephritis found that blocking the 11th and 12th dorsal and in the appearance of exacerbations. Physiolog- the first lumbar segments in patients produced an ical evidence indicates that the caliber of the ves- increase in urine and sodium chloride excretion, sels of the kidneys follows closely that of the skin but Lurz and Rohrich (51) were unable to con- vessels (Cohnheim and Roy (41), Wertheimer firmn this. Three cases of reflex anuria were (42)). Denervation in patients might dissociate thought by Haslinger (52) to be benefited by these functions as it does in animals. paravertebral injections of novocain. Splanchnic Hecht (43) found that suspensions of clumped. anesthesia also has its advocates in the treatment attenuated Stapliylococcus auretus injected into of reflex anuria (Neuwirt (53), Havlicek (54) ). the veins of rabbits caused more micotic abscesses Renal denervation in man was probably first to develop in normal than in denervated kidneys. performed by Papin (55) and by Legueu and If denervated kidneys are less susceptible to in- Flandrin (56) for relief of pain in the kidneys. fection than are normal ones, denervation might Since that time a number of urologists have per- be of therapeutic value in some conditions. formed the operation for nephralgia and painful Normal kidneys excrete intravenously injected conditions arising, from contractions of the renal Bacillus prodigiosus in a wave-like fashion. Fol- pelvis (Harris and Harris (517), Herbst (58), lowing denervation the number excreted was Hess (59), Stone (60)). Milliken and Karr 446 IRVINE H. PAGE AND GEORGE J. HEUER (34) and Hess (59) from theoretical considera- avoid too great hazard in the operation, however, tions gave the following indications for renal cases were chosen in which the urea clearance was denervation: still well above the 20 per cent level, which marks 1. Nephralg,ia, with or without accompanying entrance into the terminal stage. The onset of non-obstructive hvdronephrosis. the nephritis had occurred 16 months before op- 2. Unilateral hematuria without evidence of eration in the earliest case and 26 months in the renal pathology. latest. Evidence of the clinical condition is given 3. As an a(djunct to the remnoval of stones in by the graphic charts. the pelvis, with the hope that denervation mav prevent subsequent recurrence. METHODS OF STUDY 4. Anuria that lasts long-er than a few hours. The patients were studied in the hospital several 5. Early tuberculosis. moniths before operationi was performned. Reliance for urea clear- Rieder (61) has reported the results of unilat- studies of renal efficiency was placed on the ance test of IM0ller, MIcIntosh, and Van Slyke (65), not in the case of a suffering eral denervationi patient only because it is the most delicate test, but because from what appeared to be earlx' malignant Van Slyke, Rhoads, Hiller and Alvinig (66) have shown sclerosis. The blood pressure was 240,'1i10 mm. that in dogs it parallels the renal blood flow. The ability Hg, the nonprotein nitrogen 52 mgm., and the of the kidnieys to concenitrate urine was ascertained by urine contained red bloodI cells and albumin. the technique of Addis and Shevky (67), in whiclh onie measures the specific gravity of a 12-hour specimeni of There were no eve-ground changes. Nine months urinie passed during the latter half of a 24-hour period, after op)eration the blood pressure was 140 /90 during which the patient received no fluids. A West- mm. Hg, and( the nonproteini nitrogen in the blood phal balanice, modified by Alving and Van- Slyke (68), was was normal. The urine excreted from the de- was employed for the determinationi. Correction (69), for jnervate(l kidnev was less conicentrated thani that made, as described by Lashmet and Newburgh kidney. Subjectively the the gravity contributed by the proteini presenit in the from the other patient urine. The figures thus represent nonprotein specific was nmuclh imnproved. gravity of maximuimi conicenitrationi. IUriniary protein If, as Voihard (62) believes, nephritis is caused was estimated by the Shevky-Stafford methlod (70). by spasm of the vessels within the kidneys, pro- Red blood cells anid casts w-ere counted according to the of the blood the is maimitaine(l by the nerves to technique of Addis (71). The hemoglobini vided spasm of should relieve it and in- was recorded in terms of volumes per cenit oxygeni the vessels, denervation capacity. Plasma proteinis were ascertainied by the crease the blood flow. General experience with method of Howe (72). Plasma lipids were measured the operation of denervation indicates that inter- by the method of Kirk, Page and Van Slyke (73). Blood ruption of the nerve supply to vessels wlhich are pressure measuremenits were made at about 9 :30 a.m. restores normal tone, but that denervation with the patient in bed. On the charts these measure- spastic are averaged for conivenience in with normal tone has little effect. ments for each week of vessels represeniting them. Changes in the eyegrounids are re- Page and Heuer (63) have shown that (lener- corded as follows: (1) conistriction of the arterioles, (2) vation of the kidneys in a patient with essential arteriolosclerosis, (3) exudate, (4) hemorrhages, (5) hypertension did lnot change the renal efficiency papilledema. The estimated time elapsinig between on- set of the disease and admission to the hospital is re- as measure(I b1 the urea clearance nor (lid it sig- corded in the lowest line on the charts, as the first number nificantly reduce the ability to concentrate urine. following the word " moniths." Diets were for the most Measurements performed before the operation in- part relatively high in protein and constant in caloric dicated that renal function was normal. intake. They were supplied by a diet kitchen.' Operative procedutre Selectioni of patHeiits for operation. The techlnique of bilateral renal denervationi as we lhave Our intentioni was to select patients in whom performed it may briefly be described as follows: Unidel nephritis hadl become chrolic and progressed so general anesthesia the usual kidney incision is made upoln far that, on the basis of previous observations the right side, the perirenal fat separated, and the kidney exposed. Writh great care, in order to avoid bleedingZ, (Van Slyke, Stillman, ct aJ. (64) ), furtlher prog- ress to the terminial stage appeared certaini unlless 1 W\e wish to thank 'Miss G. Drew for her skilful man- corrected bv therapeutic miiealns. In order to agement of the diets. RENAL DENERVATION IN NEPHRITIS 447
T1.1; -rl:
FIG. 2. OPERATIVE ExPosuRE OF THE KIDNEY SHOWING THE NERVES OF THE RENAL PEDICLE.
the fat is stripped away from the kidney, which is gradu- The nerves having been identified their excision is be- ally completely freed and drawn well outside of the body. gun. Beginning upon the ventral aspect of the vessels The ureter, renal artery, and vein having been identified, exposed by drawing the kidney backward, the fan-shaped the renal vessels are stripped of all fat downward to mass of nerves is carefully freed and divided near the their point of origin. If the freeing of the vessels is vena cava. The mass is grasped, drawn upward and out- meticulously performed, the operator then will plainly ward, and the nerves stripped from the artery and vein see the sympathetic nerves coursing from their origin to up to their entrance into the kidney. Having completed the kidney. They appear as a fan-shaped, triangular the removal of the nerves from the ventral aspect of the mass upon both the dorsal and ventral aspects of the renal vessels, the kidney is drawn forward and a similar resec- vessels, the base of the triangle being directed toward tion of the nerves upon the dorsal aspect of the vessels the aorta and vena cava, the apex converging upon the is performed. These two procedures remove practically renal vessels. Upon reaching the renal vessels, the all the nerves to the kidney; but there may remain a few nerves apply themselves more closely to them and sur- which are applied to the opposing surfaces of the artery round them in a more or less well defined basket weave and vein. These vessels are therefore separated, and a plexus. search made for any remaining nerves. If found they 448 IRVINE H. PAGE AND GEORGE J. HEUER are resected. At the completion of the operation the artery and vein should appear as naked, isolated struc- tures completely stripped of all nerves. The kidney is then replaced in its fatty bed, and the wound closed. Two weeks to a month or more later a similar operation is carried out upon the opposite side. The operation has been well borne both during and after the procedure. Neither the renal artery or vein has been inj ured in any patient thus far subj ected to operation, nor has there been a single incident to mar the postoperative convalescence. Experience has shown that adequate exposure is of the greatest importance in the performance of the operation, and we have, therefore, when operating upon the left side, unhesitatingly divided the twelfth or the twelfth and eleventh ribs in order to secure it.
PROTOCOLS Case 1. (See Figure 3.) Hospital Number 8333, (E.McG.), female, age 57 years. The onset of the disease was insidious in character seven months before admission to the hospital. She complained of severe headaches, nausea and scanty passage of urine. Dr. E. Mayne found hematuria, albuminuria, edema, and the blood pres- sure elevated to 210 mm. of Hg. Rest and a low protein, low salt diet did not improve her condition, and as she appeared to be raipdly getting worse she was referred to the hospital by Dr. Mayne. Edema had' been especially severe and troublesome. The physical examination disclosed that the eyegrounds were normal except for a small fresh hemorrhage in the right retina. The heart was very slightly enlarged. The radial vessels were thickened and slightly tortuous. Pitting edema was observed up to the knees. Blood pressure was 198/104 mm. of Hg. Inhalation of amyl nitrite caused it to fall 58 mm. of Hg systolic and 40 mm. diastolic. The electrocardiogram showed all the T waves positive, conduction time 0.16 seconds, moderate left ventricular preponderance. Twenty-three months after the onset of the disease it was clear that the urea clearance was stabilized at about 50 per cent of normal and that maximum concentrating ability was 1.020. The hemoglobin rose to normal and hematuria disappeared. Total plasma protein also ap- proached normal, but the albumin fraction remained at 3 per cent. Excretion of protein in the urine fluctuated little from 5 grams in 24 hours. The blood pressure varied from 160 to 200 mm. of Hg systolic and 80 to 110 mm. diastolic. Right renal denervation was performed March 3, 1934, during the 24th month of the disease. The kidney was bound down by many dense adhesions but was found FIG. 3. UNILATERAL DENERVATION IN PATIENT WITH to be of normal size. It was moderately scarred, and CHRONIC ACTIVE NEPHRITIS. the renal arteries were smaller than normal, were beaded, and showed definite sclerosis. The masses of nerves re- did oliguria develop. The urea clearance test performed moved showed on section that the majority were non- 18 days after operation showed that it had improved myelinated, but a few myelinated nerves were present. slightly. About three months later cystoscopy was done The postoperative course was uneventful, and at no time by Dr. 0. Lowsley, and the urea clearance was per- RENAL DENERVATION IN NEPHRITIS 449
formed on specimens from the catheterized ureters. The no effect on the renal blood flow as measured by the urea results were as follows: clearance test. During the next seven nmonths, as shown by Figure 2, urea clearance and hemoglobin rose steadily. Thereafter, Cor- Clear- however, no further improvement occurred, and it became rected ance urine Urea Blood in per evident that the case had become chronic. The most con- Time volume N urea N cent of per nor- centrated urine the patient could excrete had a specific minute mal gravity of 1.012, and there was only a slight increase as- minutes mgm. mgm. sociated with the rise in urea clearance. Other data are Denervated kidney ... 30 .62 580.0 23.49 36.2 evident from the chart. Control kidney . 30 .59 528.0 31.9 Right renal denervation was performed on May 23, 1934, in the sixteenth month after the onset of the disease. The kidney was rather large and pale, measuring 12 cm. Six months after operation the urea clearance had not in length, 6.5 cm. in width at the pelvis and 4.5 cm. in changel from the preoperative level. Ability to concen- thickness. It was moderately scarred, but the main trate urine rose from 1.020 maximum nonprotein specific renal vessels were quite normal in appearance. gravity to 1.027. The protein excretion in the urine fell Twenty-one days after operation the patient was cysto- sharply to less than one gram in 24 hours. The blood scoped, and the urea clearance test was performed on the pressure fell and remained at almost 150/90 mm. of Hg, urine collected from the ureteral catheters. but has shown a definite tendency to return to the pre- operative level. Subjectively the patient feels much im- Cor- Clear- proved and has returned to her household and social ac- rected ance tivities. We have not urged the denervation of the left urine Urea Blood in per Time volume N urea N cent of kidney. per nor- Case 2. (See Figure 4.) Hospital Number 8634. minute mal (E.G.) female, aged 22 years. The onset of the disease minutes mgm. mgm. was acute three months before admission to the hospital. Denervated kidney. . 30 0.77 417.0 32.8 21.1 Control . 30 0.58 438.0 She suffered from a severe sore throat and two weeks kidney 18.8 after its onset woke up one morning to find edema of her face, hands and feet. Two days later ascites devel- Studies made during the next four months showed that oped. Hematuria and albuminuria were found, and the unilateral denervation caused no significant change in the blood pressure was 150/90 mm. of Hg. The patient urea clearance, ability to concentrate urine or the hemo- began to vomit and suffered from severe headaches; con- globin. Hematuria markedly diminished, and plasma sequently she was referred to this hospital by Dr. H. proteins rose very slightly. Excretion of protein in the Greisman. urine diminished about 60 per cent. Changes in blood Physical examination disclosed marked edema of the pressure level were not considered significant. The pa- legs and a small amount of fluid in the abdomen. In both tient was edema-f ree even though salt was allowed in eyegrounds there were numerous old and fresh hemor- the diet. Determination of plasma lipids showed that a rhages. Anemia was very marked, and the blood pres- marked fall had occurred. Lipids in 100 cc. of plasma sure was 158/98 mm. of Hg. Gastric analysis showed were: total fat 1220 mgm., total cholesterol 535 mgm., that there was no free HCI in the fasting specimen and free cholesterol 238 mgm., ester cholesterol 297 mgm., none 40 minutes after alcohol, but 33 after histamine. lipid amino-nitrogen 4.6 mgm., lipid phosphorus 14.2 Total acid in the fasting specimen was 3.1, 11.4 after mgm. and total lipid nitrogen 17.3 mgm. alcohoi and 47.0 after histamine. The pH of the serum The left renal denervation was performed on October 2, was 7.24, CO, 17.29 millimols per liter, chlorides 109 1934, about four months after the initial operation. The milli-equivalents, and total base 148.2 milli-equivalents kidney was smaller than on the right, measuring 10.3 x 5 per liter. Blood lipids were as follows: total fat 1896 x 4 cm. There appeared to be no evident change in the mgm., total cholesterol 718 mgm., free cholesterol 194 clinical or laboratory findings over those observed fol- mgm., ester cholesterol 524 mgm., lipid amino-nitrogen lowing the first operation. 12.5 mgm., lipid phosphorus 19.8 mgm., total lipid nitro- Case 3. (See Figure 5.) Hospital Number 8860. (J. gen 35.5 mgm. per 100 cc. of plasma. S.), female, age 22 years. Two months before admis- One month after admission paravertebral anesthesia sion the patient noticed that her feet and ankles were was administered by Dr. H. Wertheim at Dr. A. Alving's swollen. One month before this she became pregnant. suggestion. Novocain was injected on both sides of the Four months later she was admitted to the Presbyterian vertebrae from the ninth thoracic to the first lumbar seg- hospital because of ascites. Excretion of urine had di- ments. Two hours prior to the inj ection the clearance minished, and she complained of palpitation, substernal was 13.9 per cent of normal. Two hours after the anes- oppression and transitory loss of vision. The Wasser- thesia it was 15.2 per cent and 14.1 during the next two man test was negative. Much protein and a few red hours. Evidently paravertebral novocain anesthesia had blood cells were found in the urine. It was necessary to 450 IRVINE H. PAGE AND GEORGE J. HEUER
8634 22 yfslit. No. jHospNo E.G.8, - -~~~~~~~~~~~~~~~~~~~~~~~ Onset -Acute, edema; gro.,>ss hematuria
_ LV fffl MV 6~~~~~~~~~~~~~
C: 0 -_ U Cw 20BSSsAtS>SS d OM zv77a7rS7zez -8 cZ) 9C 0 8OB- I