Unilateral Nephrectomy in Hypertensive Disease

TnE .Jot:u.KAL OF CnoLOG't

Yol. 76, No. 6. U0.temher U)Sfi f>rintrd 1·,,.,, [r.8.A.

ll-:\"lLATEHAL >TEPTIRECTO:\lY 1'.'\ HYPEH.TK:'\i-SIYE DISEASE 1 HO\JER W. S!\UTII From the 1Jc7mrlirwnl of l'hy.siology, New York University Colteqe of Merlfrine, 2

Ne71! York, S. L

The history of cxperimcn(al hypmtcnsiou, induced hy partial occlusion of one or both renal arteries (dependiug on tlw species) or by perinephritis need;; 110 rnyim1· at thic: datf'. :\or ueed I review in detail 1he nmv extensive clinical literature reporting tlw many efforts, Bmnetimc,; sncce;c;sful, sometimes mrnuccessful, to correct hypertensin' di:,;ease in man by unilateral nephreetomy. J 1Yill ask you to hem· 11·iih me, hmn;ver, while I refer to certain sumrnaries of thi;:, literature. In l!l-±2 Braac1ch , iu what remains one of the best clinical as:,;e:,;sments of this problem, reported on I D8 hypertensive patients iu whom 'surgical operation was performed on the kidney,' and who had hecn followed for at least G mouths, thn majority for l year, and iu some in"'tances for a,; long a:,; .5 years. Hypertnrn,ion was apparently permanently relim·ed by operation for various renal lesions in ::i:i per cent of Braa:,wh's :,;cries, hut unfortunately he did not 1opecify the uature of the operations, :,;aying only that hypertension was relieved more often by nephrectomy tha11 by e(mscrvatiw: operation. In 17 instam:e:,; the pressure ,ras reduced postoperatively but returned to supernormal levelR a few 1Yeeks or months later, in some instances as long as 2 years after operation, Hence Braasch believed that no reduction of pressure for lcc1fi than 2 years could confidently he con:;iderecl a cure of the hypertensi,·e process. 1n Hl-1:1 Goldring, Chasis and I (n, 100) rcvie,Yed >l,) papers then arnilable, reporting on 76 hyperten:,;iye patiC'nts who had been :,;ubjected to nephrectomy with the hope of correcting the hypertensive proce:,;s. \Vhere the several authors eonsidered the operation to ha\·e hecn suc<·essful in -l-D per cent, we reduced the successful catq?:ory to !) per cent hccarn-;c the remainder did not fulfill ,vhat. seemed 1o u:,; to be rca,mnablc criteria for cure; i.e., if it were to be said that unilateral ncphreetomy had truly cured a definitely established hypertensive process. These criteria were, first, that def-initiyc hypertension must be established preoperntivcly and not predicated simply on oue or a fe,v blood pressure deterrninatio11s, sometimes made dming acute illnesc: ju:ot before operation, :,;econcl, that postopcratiYely the hlood pres:,;ure nrnst be reduced to the generally accepted normal range, namely 1--10/90 mm. Hg or belmv (moderate reductiow, of pres,mre in hyperten:c;ive patients not infrequently accompany non· specific therapy); and third, that the prcs:,;urc remain within normal limit;;; (1-10/00 or fwlm1·) for at leaf't one year (heeause the pre:,;sure may he temporarily reducPd to normal le,'els by a ntriety of nonspecific rncmmres, including non' Read a\ annual mee1ing of Uw Anwrican 1:hological Assoeia1ion, Boston, lvfa,ss. l\lay

:n, 1956. 'The :.;tudies carried ou\. bv t.lrn writer and his C'olleague:.; t·derred io here have been aided by grants from the ::--Jatiorrni'Henr/. Institute of the :\' ational Inst itntes of Health (H.1172, Physiolog)·J, and from the Abrahurn S. Birsh 1"1111(] and the New York Heart Association (i\ledici ne)

685

686

HOMER ,V. SM1TH

specific surgery; and even where other clillical evidence may foster optimism, the pressure may return to hypertensive levels some months after operation). Shortly after this analysis there appeared Sensenba<;h's (97) review which had been prepared independently of ours, but which, of course, covered much the same literature. Sensenbach required a 2 year normotensive followup period and found that only 7 per cent (5/75) met the requirements of cure,3 as compared with our 9 per cent. Again, in l 9 (out of 75) instances the postoperative followup was less than Sensenbach's requirement of 2 years, though normal pressure had persisted for periods ranging from a few ·weeks to 21 months. In 1948 I again reviewed this subject before the Philadelphia Urological Society (98). Using the criteria of definitely established preoperative hypertension and a postoperative reduction to 140/90 or below for at least one year, I now found 19 per cent cures (47) among 242 reported operations. 4 Simultaneously, and again independently, Sabin (96) revieffing the literature up to 1948 and using 1 year of normal pressure (140/90 or below) as his criterion of cure, concluded that ;:io per cent of 100 reported operations had been successful. The difference between Sabin's ::io per cent and my 19 per cent is that I encompassed 242 patients, many of them failures, and also excluded from the cured category some patients in whom persistent preoperative hypertension had not been firmly established. 5 The most recent full tabulation is that of Thompson and Smith-wick (105), who in 1952 again set the criteria of cure as reduction of pressure to lJ0/90 or below for 1 year or longer, and ,vho enumerated only those reports appearing since my summary of 1948. Smith-wick and Thompson cited .57 additional patients of whom 46 per cent (26) were classified as cured. This high figure may represent the better selection of patients during this 4-year period. This brings us, with a fairly uniform method of assessment, down to about 1951, and consequently I have nmr brought the tabulation (table 1) down to the most recent literature available to me. In order to complete the record I have included some reports, both positive and negative, which have been missed in preceding summaries, but excluded as far as possible any duplications. As my record now stands, since Allan Butler's (58) first report 6 in 19:)7, 575 The writer (98) later excluded 4 of Sensenbach's patients from the cured category. In 1947 Kreutzmann (83) found 54 patients in whom the pressure had been reduced to 150/90 or below for one year or longer, but he did not enumerate the failures. Kreutzmann considered his 2 patients cured, but I (98) rejected them because the last recorded pressures were 156/94 and 170/100, respectively. 5 Gasul, Glasser and Grossman (71) in 1949 found only 9 patients cured by nephrectomy for at least one year, and Gerbeaux (13) in 1950 reported that of 64 patients with adequate followup, 23 showed a 2-year cure and 16 others showed a 1-year cure, making a total for 1 year or longer of 62 per cent. 6 Quinby (94) in 1923 reported that the blood pressure decreased from 250/170 to 138/90 in a 14-year-old boy after removal of a nonfunctional hydronephrotic kidney, but postoperative observations were limited to a few days. In 1923 Quinby did not suspect that unilateral renal disease might be related to hypertension. This deduction was first made by Ask-Upmark (51) in 1929. In 1937 Butler was unaware of Ask-Upmark's paper, and his prescience in recommending nephrectomy for patient P. B. in 1935 rested on evidence that hypertension may be associated with bilateral pyelonephritis before renal insufficiency develops. von Firks (109) in 1937, unaware of Butler's work, reported that after removal of a kidney with aneurysm the systolic pressure decreased from the range of 195-245 to 130, but diastolic pressure was not recorded and there was no followup. 3

4

UNILATERAL NEPHRECTOMY IN HYPERTENSIVE DISEASE

687

patients with well established hypertension have been subjected to unilateral nephrectomy and reported in the printed record. Of this number, 26 per cent (or 149) fulfill the requirements of a minimal one-year restoration to normotensive levels (140/90 or below). This is a very good record, but if we were to sample only the last 8 years the proportion of one-year cures would still be only 25 per cent. The unsatisfactory feature of this analysis is, as I believe you will all agree, that more failures than successes probably remain unreported (for example, my colleagues advise me of some 10 unreported failures within their own experience) and hence we can take the figures quoted above only as an optimistic maximal achievement up to this date, rather than as a real one. I will hasten to admit that many of the patients on whom reports have been made less than one year after operation are 'probable' successes, and if we combine the less-than-one-year record with the one-year-or-longer record, we have a total percentage of 'probable' cures of 35 per cent between 1937 and 1956 (or 35 per cent between 1948 and 1956). However, I do not believe, as some critics have contended, that these short-term observations can conscientiously be called 'cures.' The cautious position voiced by Braasch in 1942 and affirmed by others (73, 74, 96, 97, 105) and recently reiterated by Barker (52) and by Braasch (56) 7 is well founded. Blood pressure in many hypertensive patients is very labile (7:3, 99, p. 750, 103, 108) and we have shown that it can be reduced in some patients by even the most fantastic therapy, guaranteed to have no physiological effect other than a psychic one combined with reassurance (76); and this circumstance imposes upon us the necessity to recognize a minimal period of blood pressure reduction before we can conclude that cure has been effected. I say 'us' (though I am not a urologist) because I am a member of the Association (if only an honorary one), and I hope I will embarrass no one if I say that the premature reporting, as cured, of patients who have been observed postoperatively for only 1 month, 3 months or even 6 months, reflects the impulse we all feel to report immediately to our colleagues on our successful experiments. (Those who publish short-term results generally fail to make a subsequent report, and when I have tried to obtain a followup by letter the answer has so frequently been that 'the patient has been lost sight of' that I have been discouraged in the attempt.) But we must remember that this is definitely an experimental problem, and subject to experimental errors. We will presumably be engaged in this problem for some time to come, and we sincerely hope that our patients will be too, and there is no need to hurry to conclusions. However, I think that it is now incontrovertible that an abnormality in one 7 Barker (52), supplementing an earlier report by Braasch and Barker and using 150/100 as the criterion of cure, reports a child in whom the pressure returned to prenephrectomy levels 5 years after operation. At the end of 2 years, 45 per cent of 100 patients appeared cured, but in 60 who were followed for 5 to 9 years the per cent of cures had decreased to 23 per cent, i.e. by one half. However, it is not clear that the patients in the two groups were selected by equivalent criteria. Emmett, Alvarez-Ierena and McDonald (69) give a similarly pessimistic report on nephrectomy in patients with atrophic kidney, and Graber and Shackman (15) report 2 patients in whom the pressure returned to hypertensive levels one and 9 months, respectively, after nephrectomy. An even more critical position is taken by Okulicz and Marshall (32). These writers note, however, that one apparent cure did not become evident by reduction in pressure until 2 years after nephrectomy, and they emphasize the great importance of repeated pressure determination and prolonged followup. This conservative paper merits special attention.

688

HOMER W. SMITH

TABLE 1. Unilateral nephrectomy in hypertensive disease This tabulation supplements those of Smith (98) and Thompson and Smithwick (105). Sabin's (96) summary is duplicated in large part by Smith (98) and is included here only for comparison. Data in parentheses are not included in totals.

Pressure reduced to normal Authors and year

f

Morton, '39 (30) Fitz, '40 (11) Koons et al., '40 (21) Richards, '41 (43) Platt, '41-42 (38) Rieder, '42 (44) Rachmilewitz et al., '43 (42) Winsbury-White, '43 (48) Hayward, '44 (16) MacKay et al., '44 (27) Pearce et al., '44 (35) Facquet et al., '45 (10) Hyman et al., '45-46 (19) Van Goidsenhoven et al., '46 (46) Lenegre et al., '46 (24) Lebon, '47 (23) Lobaton, '48 (26) Langeron et al., '49 (22) Bouquin et al., '49 (4) Lewis, '50 (25) Gerbaux, '50 (13) Gilliam, '51 (14) Besson, '51 (3) Arnold et al., '51 (2) Abeshouse, '51 (1) de Takats, '51 (8) Owen et al., '52 (33) Martorell et al., '52 (28) Perera et al., '52 (36) Hoffman et al., '52 (17) Puppe! et al., '52 (41) Burns, '53 (6) Pickering et al., '53 (37) Okulicz et al., '53 (32) Bourne, '54 (5) Deming, '54 (7) Schaffer et al., '54 (45) Freeman et al., '54 (12) Howard et al., '54 (18) Moore et al., '55 (29) Imber et al., '55 (20) Pastor et al., '55 (34) Verniory, '55 (47) Engel et al., '55 (9) Nesbit et al., '56 (31) Poutasse, '56 (39)

No significant reduction

Reduced but not to normal

Less than

One year

one year

or longer

-

-

-

-

-

-

(1 )• 1

-

-

-

-

-

-

-

3 1C

2 -

-

-

-

-

8

-

-

-

-

-

1

-

1 1

-

1 3 -

1

8

-

-

-

-

-

-

-

20h

-

-

-

-

-

31

-

13 16 3 3 1

-

-

-

-

-

-

-

-

1

-

-

-

-

1 (1)" 1 2 1 1 7 1 23 1 4;

2k

-

-

1 3

-

3 4

(I)m

1

-

1 1

-

1 l1 7n 1 1

-

1

-

1

-

-

-

-

2

2 1

-

1 l1

-

-

-

-

-

13

1

-

-

-

-

-

-

2 30

2 6 1

-

-

-

ltl -

1e

-

-

-

1

-

1

-

-

1 1

-

1c

-

2

-

-

1 1

-

-

-

-

1

-

-

lb

1

-

-

1 1

-

1

-

2

G89

U:\flLAT}~HAL ;,rnPHHECTOMY IN" HYPEHTENSIVE DIE\EASE

TABLJc

l. Cunt-inued

------- -1 Authors and year

Poutasse et al., '56 (40) Graber ct al., '56 (1.'i)

Snnunari0s: Smi1h, '48 (ll8) Sabin, '4,'l (06) Thompsu11 ct al., \~2 (105) Present serie,, '56 Subtotals Total reported, '37- 56 Per cr,nt eured. ':3,-.5fi Per e
No significant rc-cluction

Reduced but not to nonnHl

Pres:ure reduced to norm~~

!----~--Less than one year

One year or longer

2 ;;o

2

135 (26)

12 12:1

270

4;-;

16

47

(23)

(2])

(30)

7 27

26 75 140

12 .5] 106

50

575

26 25

Hypertension not cJcnrly established and postoperative record only 11 days. llnported by Langley nnd Platt (see \J8) as normotensive for 5 years. 0 Only one preoperative pressure reconl8d. d Aortic occhrnion (rnnnl cyst) may have contributer! to hypertension. e Nephropexy f Also reported by Howard et al (18). "Originally reported by Boyd mid Le\\ic; now reported as nonnotensive after ]2 years. h Percrn and Haelig (36) report, that in 20 patients seen at Presbyterian Hospital or in consuHat ion who were tlwught to have hypertension on the basis of nnilnternl renal disease, the pressure was not rest,on)d i.o normal by nephrectomy. Tlwsc patients constitute 'cor1 lrols' for the author's group of 7 successful opernlions and for J:-l patients quoted from the litrrntnrc Kith respect to their eriteria for nephrectom,1". As the record stands these 20 failures must be entered as sucb. ; Puppe! n,nd Alyea (41) report, \J2 patients uHdcrgoing ncphrcctomy, of whom 9 dii,d within 2 years and 17 wern lost from the record. Of the remniniug 67, 23 showed a 2,year cum. (Bu( for criteriu of cure, see comments of Okulicz and Marshall (:12).) i The writer has reclnssifi()d some of Burns' (6) Clires. 1- Okulicz nncl 1farnlrnll (32) do no1, give details on 'failttrns' and the division made here as bet,vr;en firnt, and second columns is based on I heir general comments. They required a 2-yea.r period of normal pressure, with repc:1ted determinations for cure, nnd hence con, sidered on!~· 2 of tlieir 3/i patient" as cured. 1 Ocdusion of abdomi1rnl aorta down to bifnrea1io11 of common iliacs and helm,. Tren,ted by thromboendarten,c1omy. m Alm reported by Arnold et al. (2); see not,e g. "Moore and Birchall (2D) report 12 cures but lhe ,niter has reduced this number to 7 lwen11se .J ,n,re obst,rvnd less thm1 one year, a11d i11 one prttienl, pressure was reduced nnh· to 150/ll0. Uraber and Slmckman',; 115) case 2 is pcdrnps a doubtful cure as observed 27 month;; pos(opr;ra(ively. a

b

0

kidn()y in man can prodU('C either benign or accelerated hypertensive disease.s In thi,; respect man rn,;emhles the rabbit and the rat, hut not the dog in ,Yhich bilateral arterial occlusion or perinephriti'3 is apparently necessary to produce 8 As l'outassc (:)DJ notes, ,\.,;kCpma.rk (5]) was apparently the first to point out tlwJ, unilateral renal di,;easc may caw.;e hypertension ( 'malignant nephrosclerosis'). Ask Up, mark's deduction was based on necropsy studies and preceded the definitive Jmper of Gold, blat I. Lynch, Hanzal and Summerville (lO:H) (see 72) he- some five yearn,

690

HOMER ,V. SMI'l'H

persistent hypertension. This species difference presumably reflects a quantitative and not a qualitative difference. Since we can take out this single offending organ with reasonable expectation, in well selected instances, of aborting the hypertensive process our task is cut out for us. But before inquiring into the indications for operation, let us first look at the broader problem of essential hypertension or, as most investigators prefer to call it, hypertensive vascular disease. Ellis (68) has noted that Clifford Allbutt (50) in his Hunterian Society lecture of 1895 was perhaps the first to emphasize that long-standing hypertension may exist without clinical evidence of renal disease, and to distinguish what today we call 'essential hypertension' from hypertension secondary to renal disease. And it is nmv well established that in many patients with essential hypertension the kidney shows no anatomic or functional changes. We do not even know the incidence of hypertensive vascular disease. One difficulty with nearly all statistical studies, as you have frequently been told, is that the only criterion of the disease short of the malignant phase is elevated blood pressure, and the blood pressure of many hypertensive as well as normotensive persons is subject to ·wide fluctuations and varied misinterpretations. Statistical studies generally do not separate specific causes for elevated blood pressure out of the 'essential' group, and they furthermore do not clearly distinguish between elevation of systolic pressure alone, attributable to aortic and arterial sclerosis, from the elevation of diastolic pressure which is the only diagnostic criterion of essential hypertension (7:3, 91). Puppel and Alyea (41) report an incidence of 11..5 per cent of essential hypertension in a series of 65,479 general hospital admissions at Duke; and Burns (6) reports that in IO years a diagnosis of hypertension was made in only 5 per cent of 1:38,000 general admissions to Ochsner Clinic. But these statistics do 11ot spell out the criteria for diagnosis when that diagnosis is made by many different residents and senior staff; and they are apt to give minimal figures because they nrny miss the transient hypertem,ive phase and inelude febrile and caehectic patients whose blood pressure is temporarily reduced, as well as those whose pressure falls on hospitalization and bed rest. I doubt that the incidence of hypertensive disease will ever be solYed by examination of hospital records examined in retrospect. Perhaps the most satisfactory study on living subjects is represented by that of Thompson (106) summarizing obserYations on 3;34;) employees of the .Metropolitan Life Insurance Company, ranging in duration from 5 to 25 years and upwards, and averaging 15.5 years. The ages of these employees ranged from 2:i to 62 years. Excluding those whose systolic pressure alone was elevated (indicative of arteriosclerosis) the total incidence of hypertension between the ages of 2;:3 and 62 is about 26 per cent. In the remaining 7-1 per cent the systolic pressure did not exceed 140 and the diastolic pressure did not exceed 90. There is no evidence that the diastolic pressure increases with age. Rather, according to Russek and his coworkers (95), in nonhypertensive subjects it tends to decrease with

G!ll age. 9 The aphorism that your blood presc;ure should equal 100 plus your a/!:e referred, perhap;s inaccurately, to systolic: pressure, but it has no meaning for Ow problem of hypertensive vas<'ular diseasc--ouly 26 per cent of }\Ietropolitan employees, and a smaller proportion of Russek':,; mru, developed it ,rithi11 the average life expec:tancy. VVhatever its incidence, hypertensive va:,wular disease may, so far a,.; \Ho kuow, have several diverse causes, but as yet the kidneys are not c·onvieted. I ca11 n~peat what my colleague,:; am! I (7:5, 100) said in 1~l4:3: as the reconl stanrlf, the kidney appears to be the victim and not the culprit in this disease. Thr fad we do not know the cause of hypertensi\·e va8cular disease, and nothing 11·ill be gaiued hy jumping to conclusions. 1Nhat(wcr it8 genesis, hypertensive 1°ascular diseac:e in the majority of patients runs a relatively benign course. Among 1/50 patients reported by Pcn-•ra, (9:3) the average duratioll fron1 onset to death wac: close to 20 years, though :) patients survived for pm-iods longer than 40 years. The disea1:,e is perhap8 twice as common in ,Hnncu 11B in men, bul the nbi:itetrician is now pretty well conYineed that it haB no relatiorrnhip to pregnarwy or toxemia of pregnancy (!07), or to pyelonephritis of pregnancy !G5). tensive vascular dii:ieacie appears to be a disease of the arterioles throughout the body and, a:-; we pointed out in 1941 (7!5, 99), as Yascular lesions prngreB;c.; tlw renal arterioles and the renal parmwhyma suffer along with other organs, hut renal impairment progretist~,., at an approximately equal rate in the two (GI, fi2 10 ). With respeet. to Goldblatt experimental hypertemlion, produced in animals constriction of one or both renal arteries (the requirement differs, 1 hayc noted, in different 8peries), \\'C now face a dichotomy in theory. The original Goldblatt experiment indicated that the kidney (or kidneys) "·ith compromised circulation secreted one or more noxious hypertensive agents into the blood, hut Grollman, J\luirhead and Yanat.ta (78) have now sho\\'ll that the remoYa.l of boih kidneys causes sustained hypertension in dogs which are kept alin' by peritoneal perfusion. This renoprival hypertension indicates that the kidney normally excretes, removes from the blood or otherwise neutralizes one or more noxious agents which are generated elsewhere. The liver, posterior pituitary, adrenal cortex, and e\ en the diet have been placed under suspicion almost e, erything except the gonads ha;, at one time or another been implic-a.tecl, so that one mw,1. admit that the theory of the genesis of hypertem,ive \'at,rular disea;;;e it-1 H.t Hu· moment all balled up. Ro much, then, for hyperten,;i\·e vascular disease in man and expcrimc11tul 0

0

"These data agree fairly well with those of Russek am! his coworkers (D5) wbo find thnt among 5331 living white men between the ages of 40 and 05 Yearn, the incidence of diastr,lic pressure above 06 increases from D.6 per cent in the fifth decade to 20.2 per eent i1J tbc seventh decade, remaining relatively unchanged thereafter. These figures a.re Jcmer than Thompson's perhaps becattse Rmssek et al. examined only men, ,Yhile Thompson rnpol'is on men a.nd women (the incidence of hypertension is higher in the latter) without. separntiun by sex. 1 ° Chasis and his colleagues have unreported data. on 24 nclditiona.l bypertensivc patien1 s examined with respect 1.o nnila.ternl renal blood fiow, e1c.

692 TABLE

HOMER W. SMITH

2. Pathogenesis in 149 patients in whom unilateral nephrectomy has apparently been successful in curing hypertension Pathogenesis

Pyelonephri tis a Pyonephrosis Atrophic kidneyc Hydronephrosis Tuberculosis U reteral occlusion Perirenal hematoma Renal cyst Hematogenous cyst Renal tumor Radiation sclerosis Infarct Thromboangiitis obliterans Intrarenal vascular sclerosis Aneruysm of renal artery Arterial occlusion d Not specified Total

Smith 1948

23b 4 3 5 3 2

Thompson and Smithwick 1952

7

Present series

Total

32

2

62 4 18 23 6 2 2 2 1 5 1 3 1 1 4 10 4

75

149

-

-

5 5 -

10 13 3 -

1 1

-

1 3 1 2

-

1 -

48

1 1

-

-

2

-

-

-

1

-

1 1 1 2 2 26

-

3

7

Includes 'calculus' and perinephritis. Includes one additional patient reported as normotensive after one year. c Emmett, Alvarez-Ierena and McDonald (69) find on reanalysis of records at Mayo Clinic that 37 per cent of patients with unilateral atrophic kidney (exclusive of ureter-al obstruction and cal cul us) had hypertension ( > 150/90), and nephrectomy in this special group led to good results ( <150/90) in 50 per cent of operations. They note that congenital hypoplasia, chronic atrophic pyelonephritis, obstruction, vascular occlusion, infarcts, and calculus lead to much the same pathologic end-picture and are terminally indistinguishable. Hence the writer has grouped most qualified atrophic kidneys under the single term 'atrophy.' d Includes all renal artery occlusions regardless of origin. a

b

hypertension in animals. Now we can return to our primary topic, unilateral nephrectomy, and consider the indications for operation. In the early period after Butler's (58) first dramatically successful nephrectomy in 1937, in a 7-year-old boy with calculus and unilateral pyelonephritis, many kidneys were removed on no sounder basis than slight suspicion. In 1942 Braasch (55) emphasized that the lesion must be unilateral and of sufficient severity to exclude mere coincidence with hypertension; that hypertension be of relatively recent origin, the patient generally less than 50 years of age; and, especially in adults, that retinal changes be minimal. In 1944 Sensenbach (97) emphasized that a candidate for nephrectomy should show decreased excretory function in the diseased kidney, and normal excretory function in the contralateral organ. (Qualifications with respect to duration of hypertension and age of patient are perhaps less cogent in the light of more recent observations.) In 1948 (98) I said that, in view of the low incidence of success (19 per cent), the advisability of nephrectomy must rest on conservative and recognized indi-

UNILATERAL NEPHRECTOMY IN HYPERTENSIVE DISEASE

693

cations, and not on the mere hope of reducing blood pressure. In general this conservative attitude has prevailed, but not without some criticism (29, 45), 11 and it seems that the pendulum is now in danger of swinging to the other extreme, toward what may prove to be undue optimism and the sacrifice of useful and perhaps vitally needed kidneys which are not responsible for the patient's hypertensive process. I cannot document the statement but my impression is that deaths have been precipitated by unwarranted nephrectomy, a misadventure we all hope to avoid (83). Other causes of hypertension, which must be excluded before nephrectomy is considered, are well known to you: acute and chronic glomerulonephritis, pheochromocytoma, coarctation of the aorta, Cushing's syndrome, the recently studied adrenal tumor responsible for so-called primary hyperaldosteronism ('K-losing nephritis') (63, 64), etc. As Braasch (55) early pointed out, the highest incidence of success is in unilateral pyelonephritis, but care must be exercised to exclude bilateral pyelonephritis; nephrectomy remains of very doubtful value, and possibly hazardous, when both kidneys are involved. Braasch (55) expressed the belief that the incidence of unilateral renal disease amenable to surgical treatment among hypertensive patients was only 0.5 per cent. Chasis and his colleagues (61, 62) now have available some 50 unselected hypertensive patients in whom the renal blood flow and filtration rate have been measured in the separate kidneys, and of this series only one has shown significant unilateral impairment. Smithwick (102) records only one 'Goldblatt kidney' cured by nephrectomy among twelve hundred odd patients subjected to sympathectomy. Puppel and Alyea (41) report that in a series of 65,479 hospital admissions at Duke, hypertension was present almost 3 times as frequently in patients undergoing nephrectomy as in others, implying that advanced unilateral renal disease increases the probability of hypertension; nevertheless they estimate that one can expect no more than a 2 per cent incidence of unilateral renal disease among unselected hypertensive patients. I think we may take it that the number of hypertensive patients in whom surgery is hopeful is at best 2 per cent of all hypertensive patients. In the relatively rare instances where hypertension is associated with unilateral renal disease, it is probably true, as Perera and Haelig (36) have noted, that the disease is frequently severe in intensity, and of the accelerated or socalled 'malignant' type characterized by a high diastolic pressure, headaches, convulsions, and retinopathy (except in children). The history of illness is frequently short, and any evidence of recent renal insult (trauma, infection, thrombosis, embolism) affords grounds for suspicion. There is good evidence, however, that hypertension having a unilateral origin (this applies to congenital and pyelo11 Schaffer and Markowitz (45) note that 'resistance to the operation is even now encountered in fairly sophisticated medical circles,' but of their 4 patients one was followed for one month, one for 6 months and one for 7 months. Nevertheless from the total record they concluded that one third of patients of all ages will be benefited, one third will be improved (whatever improved may mean in the long-range picture) and only one third not improved. They express the belief that it is exceptional for the pressure, after remaining normal for 5 to 6 months, to rise again. Admitted, but this does not relieve the surgeon of the responsibility of a longer followup.

694

HOMER W. SMITH

nephritic atrophy, occlusion of the renal artery, etc.) may sometimes run a relatively benign course for a period of years, only to come to urologic suspicion during an acute fulmination. The primary difficulty which the urologist faces is that of diagnosis. A single diseased kidney may elicit no symptoms to raise suspicion, and for this reason some candidates for hopeful surgical treatment may be overlooked. Total excretory function is suspect as a diagnostic measure because contralateral hypertrophy may compensate for unilateral malfunction. 12 Moreover, it is now asserted by some investigators that a guilty kidney may show no reduced function by conventional methods of testing. Consequently, even where suspicion has been raised and the patient brought to urologic attention, to indict the guilty kidney may prove to be difficult, and it is probable that a good many more kidneys have been removed on grounds of mere suspicion rather than in consequence of urologic due process and condemnation. Nevertheless, the majority of successful operations have been based on information supplied by the clinical history and conventional examination by means of intravenous and retrograde pyelography, supplemented sometimes by observations on unilateral urine flmv and dye excretion. But in many instances a guilty kidney, demonstrated to be guilty by cure after nephrectomy, has with difficulty been distinguishable from its normal mate by these conventional methods and the indictment has rested on a slight deformation of the pelvis, an unusual calcification, or some other defect so slight as to leave the urologist uneasy about the diagnosis. The implication is clearly stated by Hmvard, Berthrong, Gould and Y endt (18, 80) and implicitly accepted by others, that impairment of the blood supply to one kidney, insufficient to reduce its excretory function as conventionally measured, may nevertheless be sufficient to establish the hypertensive process. It is for this reason that aortography (101) has recently received increased attention: in many instances the evidence supplied by this newer diagnostic method has only served to confirm that gained by conventional techniques, but in other instances the method has proved its usefulness by revealing some abnormality in the renal arterial tree, generally of an occlusive nature, when intravenous and retrograde pyelography have failed to reveal definitive evidence of unilateral disease. 13 It seems to me that it would be premature to accept this implication at its face value before the presently reported cures have been fully demonstrated to be such; bilateral renal ischemia of fairly severe degree may be present in 12 Kilman, Bradfield and Simpson (82) cogently note that compensatory hypertrophy in the contralateral kidney is a favorable circumstance when nephrectomy is under con. sideration. 13 Generally the parenchyma of the ischemic organ shows no or slight pathologic changes as might be expected where the blood supply is only moderately reduced, though arteriolar necrosis ultimately attacks the unprotected kidney and other organs (9, 18, 20, 29, 39, 45, 53, 59, 84). Attention may be called to the fact, familar to all urologists but infrequently reported, that one apparently normal kidney may fail to show by intravenous pyelography on a first test, only to give a normal pyelogram on a second test (37, 39, 67, 81). Paradoxically, a 'disappearing' kidney has never been reported in duplicate clearance tests (99, p. 885£.).

CNILATEHAL SJ<;PHHECTOMY IN HYPIDRTJ<:NSIVJ<; DJSK,\SE

conge;-;tive heart failure, ill cirrhosis, and in unilateral pyelonephritis, for weeh or months without auy evidence that it initiates a hypertensive process. Sornc of the 'cures' so far reported after removal of a kidney with an aberrant arterial supply not severe enough to reduce excretory function may represent not :-,o much true cures of hypertensi\"e disease as the removal of but one strmv from the camel's baek 1 the removal of but one of several contributory factors to wha1 is still a mysterious melange. It has been said that trauslumbar aortography is the one definitive method by which occlusive renal arterial disease can be demonstrated (:)9). However, the technique has not proved to be as safe as once was thought (49, .54). Furthermore, the renal arterial tree in man (90) has many variations; in an arteriogram thec:e may look suspiciom, and yet, in view of their frequency, are probably innocent of harm in this respect. I wonder, therefore, if there is not a real danger of history repeating itself: J\fany of you will remember when every apparent kink in a ureter or inequality in pelvic size was <'harged on a statistical hac:is ab being a posc:ible cause of hypertension. It is too early to judge the meritc: and dangerR of aortogrnphy, aud in any case unless arterial anomalies conducive to hypertension haYe an unexpectedly high incidence, there will remain only a mnall proportion of decisions with respect to nephreetomy which will require the addition of this diagnostic method to conventional intravenous and retrograde pyelography. 14 J\Joreover, the urologist has not to any substantial extent used the weJJdocumented rn1ilaternl examination of the renal blood flow, filtration rate and tubular excretory function ail a diagnostic method. The reason for this is dear-it is not that the clearance methodc: are Hot simple enough in principle, but they are somewhat more tedious than conventional methods in application. Nevertheless with a third catheter in the bladder to check for leakage, it is possible to obtain very accurate collections of urine and equally accurate information on unilateral renal function by the methods described by Chasis and Redish (61) sixteen years ago, and subsequently used by Goldring and Chasis (7:3), Grabstald , Friedman et al. (70), Michie and J\Jichie (88, 89), Dean and Abels (Gfi), Wallace(] 10), Chasis aud lVIichie (60), -Weiss and Chasis (Ill), ai1d Graber and Shaekman (] 5), in the study of hypertensive disease, unilateral cornpen,,atory hypertrophy, the effects of temporary occlusion of the renal artery, the progresR of pyelonephritis, and other problems where information on function of imlividual kidneys is desired. 15 H The administration of " contrast medium in subst11ntial doses to a patient in renal failure is highly dangerous and must be avoided, contra.ry to the suggestion of et al. (86). 15 A. simple, uni[aternl endogenous creatinine clearance_ determination has been recom-mendecl by Nesbitt ((12). As Michie and Michie (87, 88) and :Michie, 2v1ichie and Ragni have pointed out, in unilateral (and unequal bilateral) pyelonephritis the urine flow the ureter is not traumatized) generally parallels the filtration rate, renal plasma flow and Tml'AH 1rnless the latter is reduced to below 10 mg/min. It is not known, however, whether this is true in other instances of unilateral imparirnent. Graber ,ind Slrnckman (15) have recently emphasized that unilateral clearance studies revealed that, of 13 single kidneys reported as normal on intravenous pyelographY, 11 were found 1-o show significantly reduced renal plasma flow and JO sho\-ved reduced filtration rate,

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The unilateral application of the clearance methods will probably not answer all questions, especially where the arterial supply is compromised, because it is known that in experimental Goldblatt hypertension in the dog the blood flow and filtration rate may return to normal levels after the clamp has been applied and persistent hypertension has been established (99, p. 702ff). Nevertheless, reduction of tubular function, as measured by bilateral diodrast Tm, is one of the earliest and most characteristic features of hypertensive vascular disease in man (75), and further exploration of unilateral diodrast Tm or PAH Tm may prove profitable in early unilateral disease. If the clearance methods fail, in the sense that a kidney with normal blood flow, filtration rate and tubular function as judged by normal standards and by its contralateral mate, can be shown to be the cause of a hypertensive process, then that fact in itself will be a substantial contribution to our knowledge of hypertensive disease. Not a single such instance has yet been recorded. I would therefore urge that in ambiguous instances unilateral clearance studies be used before surgical intervention, in the hope that this technique may prove more reliable than conventional methods, and less uncertain than aortography in arriving at a decision in such instances. I suspect that the day when we can follow the natural history of hypertensive vascular disease without medical therapy is drawing to an end. The indications for and benefits of sympathectomy have been thoroughly discussed (79, 85, 103) and it is the consensus that such benefits as are derived from this procedure are not referable to changes in the renal circulation. When I talked to the Philadelphia Urological Society in 1948 the new medicine as of that date was psychotherapy to uncover and release repressed aggression or hostility, but to my knowledge we remain without a documented report on the long-range consequences of this therapeutic measure. There followed the rice diet, and then the use of socalled 'hypotensive' drugs to lower the blood pressure, the latter requiring careful standardization on and continued observation of the patient. Now the curtain has gone up on a new era which I can briefly identify as PP (i.e., pharmacological psychiatry, psychiatric pharmacology, or psychopharmacology) identified by the use of drugs the major actions of which are presumably on the central nervous system. These drugs constitute a sort of psychotherapy per os (Rauwolfia, reserpine, chlorpromazine, Miltown, etc.). I foresee that shortly a variety of such 'tranquilizers' will be available to the physician-how many potential PP remedies will be on the market for experimental use 5 years from now I would hesitate to guess: One basis for guesswork is perhaps the history of the sulfonamides, of which perhaps a thousand have been described since 1935 (and a dozen or so remain in use); or perhaps the antibiotics, of which 3000 have been described since the development of penicillin (and of which 18, as of this week, are commercially available and officially approved). i.e. bilateral normal pyelograms do not always exclude the presence of ischemic renal disease. On the basis of clearance studies Graber and Shackman recommended against nephrectomy in 5 patients because these studies showed the presence of bilateral renal disease. In 2 of their 3 cures (cases 1 and 2) effected by nephrectomy, the faulty kidney gave an ambiguous rncord pyelographically but proved to be deficient by the clearance method.

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How many of the,;e new PP remedies will effect permanent cures of hypertensive vascular disease, and I mean cures which are permanent in the sense that the patient will need no further medication, remains to be determinecL lt will be an interesting period in cardiovascular (and psychiatric) history, and I am tempted to quote again, as I did in 1948, Trousseau's (1801-1867) injunction, "Always use the new drugs while they still have the power to heal , and Van Dyke's remark that E;ven then (in 1948) the laity ,vere amused when the cartoonist depicted the druggist holding a vial before a prospective custmner and remarking, "It has been a wonder drug for over a week now." The fact remains, however, that apart from certain identified, specific cau,'
l. A review of the record from 1937 to 1956 shows that 575 unilateral nephrectomies have been performed in hypertensive patients with demonstrated or suspected unilateral impainnent of renal function. Of this number, the blood pressure has been reduced to 140/90 or below for one year or longer in 2G per cent. This record is accepted as demonstrating that unilateral renal amenable to surgical correction, can cause either benign or accelerated h"m,ive disease in man, The record is unsatisfactory in two respects: the period on many patients has been less than one year, and probably many negative results have not been reported. 2. The true incidence of hypertensive vascular disease (elevated diastolic pressure) in man is unknown, but the best available records on living indicate that, averaging the third to seventh decade of life, this :6gure is about 2,5 per cent. In the remaining 75 per cent of the population the diastolic pressure remains below 90 throc1ghout life, and may tend to decrease with age. :3. The cause of hypertensive vascular disease remains unknuwn. On the present evidence the kidneys cannot be indicted: arteriolar disease appears to be primary, and the renal circulation and parenchyma, as in other organs, s11ffrr secondarily. 4. The theory of Goldblatt experimental hypertension is at present in a stale of fiux and throws no certain light on the origin of hypertensive vascular disease 111 man. i5. Of all pat,ients 1Yith diastolic hypertension, probably less than 2 per cent are candidates for therapeutic renal surgery. Patients subjected to renal surgery IG Butler's patient, operated on in 1935, moved away from Boston after 20 months and unfortunately lost from the record. Severn! long period records arc now available: Boyd and Lewis: 1937-52 (18); Leadbetter and Burkland: 1938-50 (57); Van Goidsenhoven: 2 pa.tieuts, eai'h 9 yearn (46), Besson: Hl4J-51 (3); and Okulicz and Marshan: 2 patients, 10 and 7 respective]:,- (32), It 1vill be very valuable when more long period followups can be

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for correction of hypertensive disease should be followed for a minimum period of one year and the diastolic pressure should be reduced to or below 90 mm. Hg (or systolic and diastolic pressures to or below 140/90) before they are classified as cured. 6. As of this date, renal surgery (generally nephrectomy), even though limited in applicability, is the only demonstrated apparently permanent cure for so-called essential hypertension. 7. Conventional urologic examination is indicated in hypertensive patients generally only when strong suspicion is raised by history, physical examination and routine laboratory examination. 8. ·where unilateral renal disease is responsible for hypertension, it is to be anticipated that the responsible kidney will generally be discovered by the careful a.nd critical application of conventional urologic methods. More precise criteria remain to be established, but in the meantime it is urged that in ambiguous instances these methods be supplemented by the unilateral measurement of filtration rate, renal plasma flow and TmPAH· 9. In the present enthusiastic phase the urologist may find himself pressed to intervene surgically against his better judgment. 10. He has at his command the only known cure for hypertensive disease (however limited it may be in applicability to the general hypertensive population); and in the face of widespread, diverse, uncontrolled and sometimes uncontrollable therapeutic experimentation, he is urged to observe every conservative measure in its application and interpretation. Even in the presence of obvious unilateral disease, nephrectomy remains an experimental procedure and subject to experimental error. REFERENCES TO TABLE 1 1. Abeshouse, B. S.: Aneurysm of the renal artery: report of two cases and review of the

literature. Urol. and Cutan. Rev., 55: 451, 1951. 2. Arnold, M. W., Goodwin, W. E. and Colston, J. A. C.: Renal infarction and its relation to hypertension. Urol. Survey, 1: 191, 1951. 3. Besson, J. H.: Nephrectomy for hypertension. The second reported ten-year cure. Surgery, 30: 570, 1951. 4. Bouquin and Imbert: Hypertension grave par hydronephrose gu6rie par nephrectomie. La Semaine des Hopitaux, 25(1): 522, 1949. 5. Bourne, W. A.: Nephrectomy in hypertension due to renal artery infarction. Brit. Med. J., 2: 271, 1954. 6. Burns, E.: Unilateral renal disease and hypertension. Calif. Med., 79: 415, 1953. 7. Deming, Q. B.: Association of polyuria and albuminuria with hypertension of unilateral renal origin. Arch. Int. Med., 93: 197, 1954. 8. de Tatakts, G.: In discussion of Smithwick. (104, p. 305). 9. Engel, W. J. and Page, I. H.: Hypertension due to renal compression resulting from subcapsular hematoma. J. Urol., 73: 735, 1955. 10. Facquet, M. J. and Ricordeau, P.: Hypertension art6rielle permanente par lesion pyclo-renale unilaterale (hydroncphrose). N ephrectomie. Gu eris on depuis deux ans. Soc. Med. hop. de Paris, 4E Serie 61: 110, 1945. 11. Fitz, R.: Hypertension and its peculiarities. The Mississippi Doctor, 17: 531, 1940. 12. Freeman, N. E., Leeds, F. H., Elliot, W. G. and Roland, S. I.: Thromboendarterectomy for hypertension due to renal artery occlusion. J.A.M.A., 156: 1077, 1954. 13. Gerbeaux, A.: L'hypertension arterielle d'origine renale curable par nephrectomie chez l'homme. Semaine h6p. de Paris, 26(1): 715, 1950. 14. Gilliam, M. R.: Perirenal cyst associated with hypertension: report of a case. J. Urol., 66: 661, 1951. 15. Graber, I. G. and Shackman, R.: Divided renal function studies in hypertension. Brit. Med. J., 1: 1321, 1956.

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l (i. Hayward, W. G. · Rena.I surgery as a cause of renal ischernia. J. U rol., 51: 486, l\l44. 17. Hoffman, B . .J., Bailey, M. K. and Fort, C. A.: Unilateral pyelonephritrn, accompanied by hypert,•,rnion relieved by nephrectomy ..J. T.Trol., 67: 132, 19.52. 18. Howard, J.E., Berthrong, M., Gould, n. M. and Yenclt, E. R.: Hypertension rnsiilting from unilaternl renal vascular disPase and its relief by nephrectomy. Bull . .Johrrn Hop kins Hosp., 94: .51, 19.54. HJ. Hyman, A. and Lei1.tir, H. E. · Essential hypertension associated with iinilnter:d disease of the kidneys. J. ML Sinai Hosp., 12: 33.5, 1945--46. 20. Imber, 1. nnd Clymer, R. H.: Obstruction of the nrna.l artery producing nrnl.igrw.nl. h~·pertension. New Eng, ,L MerL, 252: 80l, 1955. 2.l. Koons, K. 'i\11. and R.uch, M. K.: Hyperterrnion in a 7 year old girl 1i-itl1 Wilm,;' ltunor rnlieved by nephrectorny. J.A.M.A,, 115: 1097, 1940. 22. L,1ngeron, L., .\/olf, V., Langeron, P. and Duriez, J .. ~6phropathic uniJaterale avec hypertension arterielle ..Amelioration de la tension cle la fonction r6nalc a.pres n(phrectomic .J. d'Urol., 55 suppl. No. 10: 804, HJ49. 2:3 Lebon, J.: Nephrite avec hypertension trnit{e par nephrectomie Soc. '\led. h6p de Paris, 4E SeriP, 63: 449, 1947. 2°l. Lenegre, J. a.nd De.sgeorges, H.: Un ca.s d'hypertension arterielle con;;,;c u ti ve a unc ltsion renale Lmilatera.k e( gucrie par la nephrectomie. Arch. des i\faladins du Coeur et de.s Viasseaux, 39: 30, 1946. 25. Lewis, D. B.: Unilateral kidney disease and hypertension. Urol. arnl Cutan. Rev. 54: ;343, 1950. 2(\, Lobaton, C.: Urological surgical. treatment. of arterial hypertfmsioD. of five cases. Urol. and Ctttan. Rev., 52: 86, 1948. 27. ·LVfacKay, Proctor L. D. and Roome. N, vV.: Hypertension after removal of :, renal calculus. Can, M A. 50: 328, 1944. 28. Martorell., F., Alonso, Martorell, A. and Roca de Vinyals, R.: Afrofia renal unilateral e hiperte1rnion diastolica. J. int. de Chirurgie, 12: !01, 1952. 29. Moore., C. and Birchall, IL: Um1wal case of hypertension due to unilateral pyeJonephritis. Ochsner Clinic Hepts., 1: 2.5, 19,55. :JO. Morton, W. P.: In cli.scussion of CrabtreR and .Prien (6,5). :n. 1\'esbit, R. M. and Crenshaw, W, B.: Aneurysm of the renal artery. ,J, UroL. 75: :380, 1956. :)2. Okulicz, S. ,J, aml \farshall, V. F.: Nephrectomy and hypertensiou ..\m. J. 8urg., 86; ±5, HJ5,l. :3:J. Owen, Vil. F.,. Jr. a.nd Pearlman, C. K.: Hypertension due to thrombosis of !be renal nrtery: report of a case in which a cure was obtained by nephrectomy . .J. Urol., 68: .l J, UJ-52. :H. Pastor, B. H., Myerson, R. M., Wohl, G. T. and Rouse, P, V.: Hypertension a.ssociatcd with rennl artery ,rneurysm and relieved by nephrectomy. Ann. Int. j\fod., 42: 1122, 19,55. ;.;.s. Pearce, A, E., Bower, J. 0. and Burns, J. C.: Uncomplicated, solitary, serou~ renal cyst with hyperte11sion relieved by nephrocystectomy. Ann. Int. Med., 20: D94, 1944. 36. Perera, G. A. and Flaelig, A. W.: Clinical clmracteristics of bypertension ,rnsociatl,d with nnilateral renal disease. Circulation, 6: 54!), 1952. :n. Pickering, G. W. and Heptinstall, R.H.: Nephrectomy and other t.reatmen(. for hyperte1rnion in pyelouephritis. Quart. J. Med. (new series) 22: 1, 19.53. :18 Platt, R.: In discussion on the kidney and hypertension; Freie. Roy. Soc. "\le(L, 35; 017. 1941--±2. :3!). Pontasse, E. F_: ()ccl11,sion of a renal artery as a cause of hypertension. Circulation, 13: :n, ID.56. 40, Pol1tasse, E. Ji, and D11stan, H.: Urologic causes of hypertension. I. Hypertension due to renal artery lesion.-;, Cleveland Clinic Quart., 23: 3, 1956. 41. Puppe], A. D. and Aiye,i, K P.: Hyperterrnion and the surgical kidney .J. [Trol .. 67: 4::33, 1952. 42. Rachmilewitz, ::vr. and Brnm1, K.: Nephrectomy in hypertension H.ssociated with unilateral kidney disease. Cardiologia., 7: 304, 1!)43. 4:3. Richards, G. G.: Unilateral renal tuberculosis associated with hypertension . Ann. int. Nled. [15]: :12'±, 194]. 44. Rieder. vV.: Sonderstellung arterio-veniiser aneurysmen der nierengefiiffe im rnhmen operntiver hehandlung schwerer herz-Kreislaufschiiclen beim arterio-veniisen aneurysma. Chirnrg, 14: 609, 1942. c!ii. Scbaffer, A. J. and :i\ln.rkowitz, ;\-1,: Hypertension treated by nephreetomy: ,1 report of ·l additional cases and a re-evaluation of prognosi,, and criteria for operntiun. Am. ,J. Med 227: ,117, 1\)54. Van Goidsenhove11, F. and Vandenbrnuck, J.: Formes cum.hies de ] 'hypertension ,·;\nale cl1irurgicale nu urologique (dix cas personnels). Presse m0d., 54: 52, J\)46. 47. Verniory, A.: Relation c!'nn ens d'hypertension avec atrophie n'.rrnle nnilnL6rnie. Gn0rison par nephrectomie. 1n: Govaert.s, P., Livre J1.1bilaire, p. 194, 1955. 48. Winsbnry-White, l-1.. F, :Four cases of hypertension which benefited from -~urg-ical. procndure.s. Brit. J. lJrol .. 15: DO, Hl43,

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REFERENCES TO TEXT 49. Abeshouse, B. S. and Tiongson, A. T.: Paraplegia, a rare complication of translumbar aortography. J. Ural., 75: 348, 1956. 50. Allbutt, C.: Senile plethora or high arterial pressure in elderly persons. Hunterian Soc. Trans., p. 38, 1895~96. 51. Ask-Upmark, K: Uber juvenile ma1igne nephrosklerose und ihr verhaltnis zu sti:irungen in der neirenentwicklung. Acta Path. et Microbial. Scand., 6: 383, 1929. 52. Barker, N. W.: Hypertension and unilateral renal disease. Med. Clinics N. Am., 35: 1041, 1951. 53. Bauer, H. and Fobes, G. L.: Unilateral renal artery obstruction associated with malignant nephrosclerosis confined to the opposite kidney. Am. Heart J., 44: 634, 1952. 54. Baurys, W.: Serious complications associated with the newer diagnostic methods in urology. J. Ural., 75: 846, 1956. 55. Braasch, W. F.: The surgical kidney as an etiological factor in hypertension. Can. M. A. J., 46: 9, 1942. 56. Braasch, W. F.: End results following nephrecomy in patients with hypertension. J. Ural., 68: 6, 1952. 57. Burkland, C. E., Goodwin, W. E. and Leadbetter, W. F.: The cure of hypertension by nephrectomy. Surgery, 28: 67, 1950. 58. Butler, A. M.: Chronic pyelonephritis and arterial hypertension. J. Clin. Invest., 16: 889, 1937. 59. Castleman, B.: Causes of essential hypertension in man as elucidated by anatomicopathological investigation in humans. (104, p. 102). 60. Chasis, H. and Michie, A. J.: See (74). 61. Chasis, H. and Redish, J.: Effective renal blood flow in the separate kidneys of subjects with essential hypertension. J. Clin. Invest., 20: 655, 1941. 62. Chasis, H. and Redish, J.: Function of the separate kidneys in hypertensive subjects. Arch. Int. Med., 70: 738, 1942. 63. Conn, J. W.: Aldosterone in clinical medicine--past, present, and future. Arch. Int. Med., 97: 135, 1956. 64. Conn, J. W. and Louis, L. H.: Primary aldosteronism, a new clinical entity. Ann. Int. Med., 44: 1, 1956. 65. Crabtree, E. G. and Prien, E. L.: The nature of renal injury in acute and chronic colon bacillus pyelonephritis in relation to hypertension: a combined clinical and pathological study. J. Ural., 42: 982, 1939. 66. Dean, A. L. and Abels, J.C.: Study by the newer renal function tests of an unusual case of hypertension following irradiation of one kidney and the relief of the patient by nephrectomy. J. Ural., 52: 497, 1944. 67. Donnelly, B.: Circulation in the kidney. Lancet, 251 (2): 362, 1946. 68. Ellis, A.: Discussion on the kidney and hypertension. Proc. Roy. Soc. Med., 35: 309, 1941-42. 69. Emmett, J. L., Alvarez-Ierena, J. J. and McDonald, J. R.: Atrophic pyelonephritis versus congenital renal hypoplasia. J.A.M.A., 148: 1470, 1952. 70. Friedman, JVI., Selzer, A., Kreutzmann, H. and Sampson, J. J.: The changes in the blood pressure and in the renal blood flow and glomerular filtration rate of hypertensive patients following unilateral nephrectomy. J. Clin. Invest., 21: 19, 1942. 71. Gasul, B. M., Glasser, J.M. and Grossman, A.: Extreme hypertension in a child cured by nephrectomy. J.A.M.A., 139: 305, 1949. 72. Goldblatt, H.; Experimental hypertension. Am. J. Med., 4: 100, 1948. 73. Goldring, W. and Chasis, H.: Hypertension and Hypertensive Disease. New York: The Commonwealth Fund, 1944. 74. Goldring, W. and Chasis, H.: Sympathectomy and unilateral nephrectomy in the treatment of hypertensive disease. Med. Clinics of N. A., 33: no. 3,751, 1949. 75. Goldring, W., Chasis, H., Ranges, H. A. and Smith, H. W.: Effective renal blood flow in subjects with essential hypertension. J. Clin. Invest., 20: 637, 1941. 76. Goldring, W., Chasis, H., Schreiner, G. E. and Smith, H. W.: Reassurance in the management of benign hypertensive disease. Circulation, 14: 260, 1956. 77. Grabstald, H.: Renal hemodynamics in clinical urology. J. Ural., 66: 19, 1951. 78. Grollman, A., Muirhead, E. E. and Vanatta, J.: Role of the kidney in pathogenesis of hypertension as determined by a study of the effects of bilateral nephrectomy and other experimental procedures on the blood pressure of the dog. Am. J. Physiol., 157: 21, 1949. 79. Hoobler, S. W., Manning, J. T., Paine, W. G., McClellan, S. G., Helcher, P. 0., Renfert, H., Jr., Peet, M. M. and Kahn, E. A.: The effects of splanchnicectomy on the blood pressure in hypertension. Circulation 4: 173, 1951. 80. Howard, J. E.: Hypertension due to vascular lesions of one kidney--its significance to the problem of hypertension in general. Am. J. Obst. and Gynec., 68: 1212, 1954. 81. Kaufman, S. A.: The acceleration of delayed excretory urograms with ingested ice water. J. Ural., 74: 243, 1955.

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