Observations
on
Renal Hypertension
The Role of Renal Biopsy
By VICTOR VERTES, M.D.,
AND
JAMES A. GRAUEL, M.D.
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cases with less than 1 year follow-up, and it
is possible also that many successfully treated
cases have not been published. It is impossible to determine how imany of the treated
patients had bilateral renal disease with one
kidney being the more severely affected. In
such cases the removal of the more diseased
kidney would not be expected to result in a
cure of the hypertension.
To determine that only one kidney is involved, the major diagnostic procedures, at
present, involve either renal aortography,6' 10,
17-19 renal split-function studies, or both.13 20,
21 The incidence of strictly unilateral renal
disease varies greatly in the reports from different clinies.5
It is difficult to assess the significance of
arteriosclerotic plaques involving the renal
arteries, demonstrated by aortography. Eyler
and associates22 implied that probably more
than one third of such lesions are not funetionally significant.
Renal split-function studies have been of
limited value in predicting the outcome after
surgical intervention.21 23 25 However, they
provide the only currently available guide to
the functional significance of stenosis or obstruction of a main renal artery.
It is possible for intrarenal arterial and
arteriolar sclerosis to progress more rapidly
in one kidney than in the other. This entity
is probably more common than the published
data would indicate and can give renal splitfunction results consistent with unilateral
renal disease.
Moritz and Oldt26 demonstrated in 1937
that renal arterial and arterioloselerosis were
present bilaterally at autopsy in the majority
of cases of hypertension and virtually absent
from an equal number of nonhypertensive
patients. These authors concluded that their
data provided evidence for the "Goldblatt
I NTEREST in unilateral renal disease as a
possible cause of human hypertension
originated with Goldblatt 's classic experiments.' In 1937, Butler- reported the clinieal
cure of hypertension following nephrectomy
in two cases of unilateral, pyelonephritis with
vascular disease in children. In recent years
it has been recognized that many cases of human hypertension are on the basis of unilateral renal disease,3-7 and unilateral nephreetomy has been performed in many such eases.
When ischemia has been found due to stenosis
or partial obstruction of a main renal artery,
repair of the vascular lesion in various ways
(without nephrectomy) has been practiced,
with favorable results reported in some
cases.3-'3
The number of hypertensive patients
treated by unilateral nephrectomy or repair
of the main renal artery has been mounting
precipitously. In a review article5 it has been
stated that "there are upwards of two million subjects with undiagnosed renal artery
stenosis in the United States of America."
The implication of this, and of similar statements, is that all of these persons are potential candidates for surgery.
Great interest in the development of technics
to detect unilateral renal disease followed the
reports of Smith'4' 15 and of Thompson.16
Smith15 found that 26 per cent of 535 patients
had been cured of hypertension as a result of
unilateral nephrectomy, but cautioned that
many unsuccessful cases probably had not
been reported. However, he eliminated nmany
From the Division of Medicine, Mount Sinai Hospital, Cleveland, Ohio.
Supported in part by a grant from the Norther n
Ohio Chapter of the National Kidney Disease FouIndation, by UT. S. Public Health Service Grant 62-92H-7308, and by a Research Grant from the Jewish
Community Federation of Cleveland, Ohio.
536
Circulation, Volume XXVIII, October 1963
RENAL BIOPSY IN RENAL HYPERTENSION
mechanism " (unilateral or bilateral renal
isehemia) in human essential hypertension.
It is our contention that strictly unilateral
renal disease as a cause of hypertension is not
so common as present reports would indicate,
and that bilateral renal biopsy serves. as the
blest guide for final decision regarding surgical
intervention in cases in which the split-funetion study indicates, the probable existence of
unilateral renal disease.
Material and Methods
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Thirty-six hypertensive patients were admitted
to the Metabolic Unit of Mount Sinai Hospital of
Cleveland. These patients were unselected admissions from the Hypertension Research Clinic.
Routine laboratory studies were performed. In
addition, determination of renal function, intravenous pyelography, and studies to rule out other
causes of hypertension were carried out.
Transfemoral aortography wa.s performed by
means of the technique of Seldinger.27 Renal splitfunction studies were performed, with some modification, as described in detail by Stamey et al.21
Inulin and paraaminohippurate (PAH) clearances were determined with a 4-per cent urea
diuresis rather than the 8-per cent concentration
used by Stamey. This modification of the te-chnic
produced an adequate urine flow and decreased
the post catheterization morbidity. It was possible
in each instance to obtain three consecutive urine
volumes that were within 6 per cent of each other
when expressed as the ratio V1/V2.
Results of renal split-function studies were expressed as the ratios V1/V2 and U1/U2, as described by Stamey et al.21 V represents the. volume
of urine in milliliters per minute, and U represents
the concentration of inulin in milligrams per cent
in the urine. In the ratio V1/V2, V2 always represents volume in milliliters per minute from the
kidney with the greater rate of flow of urine.
U1/U2 is the ratio of the concentration of inulin
in the urine specimens that corresponds to the
ratio V1/V2. Thus, in both ratios, the denominator
is always the value obtained for the kidney having
the greater rate of flow of urine.
Bilateral percutaneous renal biopsy specimens
were obtained from all patients. These were interpreted independently by the hospital pathologist
and by Dr. Harry Goldblatt. They did not know
the indications for biopsy or the clinical history.
The specimens were subsequently reviewed and
compared again by Dr. Goldblatt without benefit
of the clinical data.
Results
Thirty-six aortograms were performed in
Circulation, Volume XXVIII, October
1963
537
this group of hypertensive patients. All of
these showed evidence of some arterial disease.
Eleven (31 per cent) indicated an arteriosclerotic plaque in the region of the renal arteries,
or showed some degree of stenosis, with poststenotic dilatation of the renal artery.
Ten of the patients (28 per cent) had renal
split-function studies that were consistent
with the funetional changes characteristic of
unilateral renal ischemia.21 A combination of
a significantly decreased volume of urine with
a significantly increased concentration of inulin in the urine from the affected kidney was
considered suggestive of unilateral renal
isehemia. A urine volume ratio (V1/V2) less
than 0.80 and an inulin concentration ratio
(U1/U2) greater than 1.12 were considered
significant. A combination of these two was
necessary for the diagnosis of unilateral renal
isehemia. Bilateral renal biopsies were performed in all cases; all the specimens showed
bilateral renal disease and most of them exhibited severe arterial and arterioloselerosis.
The data from 10 patients, in whom the
renal split-function tests were positive for
unilateral renal disease are summarized in
table 1. The corresponding bilateral biopsy
specimens revealed no significant difference
between the two kidneys in the degree of intrarenal vascular disease.
One of these 10 eases deserves, special comment because the results, of the renal splitfunction studies unequivocally indicated severe ischemia of one kidney, and the biopsy
specimens showed equally severe, bilateral,
intrarenal vascular disease. In spite of the
latter finding, the decision was made to remove the more diseased of the two kidneys.
The history of this patient (L.W.) is reported
in more detail below.
Case Report
is
a
L.W.
54-year-old woman who was first seen
in the Out-Patient-Department of Mount Sinai
Hospital of Cleveland in 1961. Blood pressure observations during that year ranged from 150 to
210 systolic over 90 to 130 diastolic. In 1962 she
was admitted to the Hypertension Research Clinic.
Multiple baselin-e blood pressures were obtained,
aniid the average sitting blood pressure was 199/
123. Her past history was noncontributory and the
0538
VERTES, GRAUEL
Table 1
Ten Hypertensive Patients with Positive Criteria for Unilateral Reno vascular Disease
IJI/U2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Name
Average B.P.
H.D.
171/117
V,/V2
R/L
.577
UI/U2
(Inulin)
1.12
Aortogram
Diffusely narrowed bilaterally,
poor
nephrogram
Biopsy
Arterioloselerosis & pyelonephritis,
marked
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J.B.
215/146
R/L
.444
1.78
Right plaque with PSD;*
atherosclerosis
Arterioloselerosis & arterial
sclerosis & pyeloinephritis, moderate
J.B.
209/111
R/L
.728
1.12
Right plaque with PSD
F.R.
189/107
R/L
.646
1.55
Atheroselerosis, nionvascular
measses bilaterally
Arterioloselerosis & arterial
sclerosis & pyelonephritis, mloderate
Arteriolosclerosis & arterial
sclerosis, moderate
A.B.
220/120
R/L
.630
1.14
Atherosclerosis
D.H.
217/117
L/R
.623
1.59
Atherosclerosis
Arterioloselerosis & arterial
sclerosis, moderate
Arterioloselerosis, severe
I.T.
215/125
R/L
.672
1.39
Left dilated distally, right
Arterioloselerosis, marked
possible narrowing
K.D.
220/120
L/R
.590
1.83
Right narrowed with PSD
Arterioloselerosis &. pyelonephritis,
marked
L.M.
198/113
L/R
.767
1.22
Atherosclerosis
L.W.
199/123
R/L
.274
2.19
Atherosclerosis
Arterioloselerosis & arterial
selerosis, slight
Arterioloselerosis & arterial
sclerosis, marked
*PSD, poststenotic dilatation.
famiily history was essentially negative for hypertension. She was admitted to the hospital and the
results of aortography, of split renal-function
studies, and of bilateral renal biopsy are recorded
in table 1.
The aortogram revealed no obstructive lesion of
the large arteries. Renal split-function studies were
unequivocally positive for functionally significant
unilateral renal disease. This patient was therefore
considered a suitable subject for unilateral nephreetomy according to the criteria in the current
literature.3, 6, 8, 10-13, 17, 21, 23, 25, 28-30 However, patient L.W. had evidence, on renal biopsy, of
bilateral diffuse intrarenal vascular disease. Despite the renal biopsy findings, patient L.W. was
subjected to right nephrectomy in order to study
the effects of nephrectomy when bilateral disease
is present, more marked in one kidney than the
other. The pathologic diagnosis on the nephreetomy specimen was diffuse intrarenal arterial and
arterioloselerosis. The patient tolerated the procedure well and during the postsurgical hospitalization her blood pressure stabilized at 140 to 150
systolic and 90 to 100 diastolic. She was discharged
from the hospital and again followed in the clinic
where successive blood pressures were obtained at
2-week intervals during a period of 4 months. The
average blood pressure .after nephrectormiy was
190/124, essentially the sanme as before the operation. The patient is now receiving Ismelin* to
control her hypertension.
Discussion
In the establishment of the criteria for the
diagnosis and the surgical treatment of patients with renovascular hypertensioni, several
pertinent problems arise. The first, and probably the most important one, is the establishment of the existence of hypertension. Most
observers are aware of the natural fluctuations
of blood pressure that can occur in an individual.'4 However, these fluctuations are not
ordinarily taken into account.3 8,11 Some authorities claim that 50 per cent of males and
60 per cent of females over the age of 40 have
hypertension.31 Others, assert that 26 per cent
of adults in the United States have essential
hypertension. Master et al.32 stated that two
thirds of females past the sixth decade, and
two thirds of males past the seventh decade
have hypertension. Therefore, if one were to
*Ismelin
(Guaniethidine),
Ciba.
Circulation, Volume XXVIII, October 1963
RENAL BIOPSY IN RENAL HYPERTENSION
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rely solely oi l)lood pressure ineasurements,
using 140/90 as the upper limits of normal,
ease selection for hypertensive studies could
potentially involve one of four young adults
and two of three older patients in the United
States!
It is well established that radiographic
studies of the arterial tree may show evidence
of anatomic lesions such as arteriosclerotic
plaques, or other vascular irregularities, in
patients with or without hypertension. Sutton
and associates18 found that 10 per cent of 260
patients had evidence of renal artery stenosis
on aortography. At the Cleveland Clinic, in
6 years, 617 aortograms were performed; 173
(28 per cent) showed occlusive disease of the
main renal artery or its primary branches.'9
Morris et al.'7 28, 29 found that 55 per cent of
642 aortograms showed aortic and large abdominal vessel disease. Therefore, if one were
to accept a casual blood pressure determination above 140/90 as evidence of hypertension
and would then perform an aortogram, there
would be a good chance of demonstrating some
sort of anatomic abnormality of the same type
that occurs in normotensive individuals. It is
generally not possible unequivocally to
establish the functional significance of an
arterial abnormality demonstrated by aortog-
raphy.8' 22, 25
The frequency of abnormal aortograms,
associated with elevated or normal blood pressure, makes it mandatory to look more critically at this method as a mean of determining
the necessity of surgery to cure the hypertension and emphasizes the danger of diagnosing
and treating hypertension on the basis of a
casual determination of the blood pressure.30
It is the opinion of the authors that renal
split-function studies are necessary to help
establish the significance of a renal vascular
abnormality found by aortography. It is relatively well established that the main functional defect in renovascular hypertension is
an increased tubular water resorption due to
decreased renal blood flow.2' When diffuse intrarenal arterial disease is present, however,
the results of renal split-function studies may
be equivocal. The same hemodynamic changes
Circulation, Volume XXVIII, October 1963
539
that occur with hypertension seconidary to
main renal artery stenosis can also be produced by diffuse, bilateral, intrarenal, obliterative sclerosis in arteries and arterioles. The
development of these lesions may not be symmetrical; therefore, function studies may
point to greater involvement in one kidney
than in the other. These changes can then be
mistaken for unilateral renal artery disease.
We believe that our patient, L.W., falls into
this category. The dilemma of such a situation
can easily be solved. If biopsy of the supposedly "good" kidney shows advanced vascular disease, the basic abnormality is probably diffuse, bilateral, intrarenal, arteriolar
disease. However, if the biopsy specimen is
normal, or shows only slight vascular disease,
the functionally significant lesion is more
likely to be in the main renal artery and potentially amenable to surgical intervention.
The results of biopsy in our 36 patients
sbow that in all specimens there was some evidence of intrarenal vascular disease. The
group included patients with positive aortograms, as well as abnormal renal split-funetion tests, and it is our belief that removing
active renal tissue from such individuals is
contraindicated.
Conclusions
Thirty-six patients with hypertension were
studied with aortograms, bilateral percutaneous renal biopsies, and renal split-function
tests. It is concluded that hypertension due
to unilateral renal ischemia is a disease entity
in which anatomic and functional changes
point to a lesion in one kidney or in its blood
supply; the contralateral kidney is normal
or, at worst, has only minimal vascular disease. It is also concluded that when unilateral
renal isehemia is suspected, an aortogram
should be performed first. If a lesion is evident, a biopsy specimen of the contralateral
kidney should then be obtained. If vascular
changes are absent, or minimal, a renal function study would then define the importance
of the anatomic lesion. If both aortogram and
function studies are abnormal on the same
side, and the contralateral biopsy specimen
5 40
VERTES, GRAUEL
shows a tiorinal picture or olily iiiiiiiilal vascular changes, surgical intervention is indicated. The incidence of suclh situations is
probably much rarer thani published studies
indicate.-0
Acknowledgment
We wish to express our thanks and appreciation
to Dr. Harry Goldblatt and Dr. Harold Gold, for
reviewing biopsy specimens, and to Dr. Mortimer L.
Siegel, for con-structive criticism and review of the
manuscript.
We are indebted to Drs. A. Bennett, H. Cohen,
J. Galvin, S. Hantman, L. Kest, R. Newman, M.
Shaw and the, House Officers of Mount Sinai Hospital
of Cleveland for their participation in the study.
The technical assistance of Mr. Henry Synor and
staff is gratefully acknowledged.
logical finidings ill twvenity-five cases. New
England J. Med. 267: 794, 1962.
9. BROWN, J. J., PEART, W. S., OWEN, K., ROBERTSON, 1J. T., AND SlUTTON, D.: Diagnosis and
treatnient of reiial-artery stenosis. Brit. M.
J. 2: 327, 1960.
10. POUTASSE, E. F.: Diagnosis and treatment of
occlusive renal artery disease and hypertension. J.A.M.A. 178: 1078, 1961.
11. MORRIS, G. C., JR., CRAWFORD, E. S., COOLEY,
D. A., SELZMAN, H. M., AND DE. BAKEY, M. D.:
Renovascular hypertension: Experience with
12.
13.
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Art and Science in Medicine
When we compare science and art in medicine we find that, to use a mechanical analogy,
the former is enormously the more efficient engine where it is available. Its only necessary fuel is knowledge-given knowledge and the appropriate case, success with a very
small margin of error is certain. Medical art on the other hand is as an engine extravagantly inefficient and needs every faculty of the doctor to get it to work at all. This is why
it is that he has not only to be taught but to be trained. By teaching I mean the imparting
of knowledge, and for that we are dependent on our teachers; by training I mean the cultivation of aptitude, and for that we are dependent on our opportunities and ourselves. It
is here that we see most clearly the difference in the requirements of experimental science
and of an art. The exactitudes of science call for the elimination of human faculty as far
as possible; the lack of exactitude in the practical art calls for the use and expansion of
human faculty as far as possible. It would be a poor physiologist who used his eye to
estimate the weight of guinea-pigs or his tongue to measure electric currents; but the
physician who makes the fundamental observation of medicine and says, "My clinical
instinct tells me that man is ill," though he uses an instrument with an error deplorably
great, uses the only instrument capable of making any record at all, and will do well to
keep it in repair.-The Collected Pap,ers of WTilfred Trotter, F.R.S. London, Oxford
University Press, 1946, p. 96.
Circulation, Volume XXVIII, October 1963
Observations on Renal Hypertension: The Role of Renal Biopsy
VICTOR VERTES and JAMES A. GRAUEL
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Circulation. 1963;28:536-541
doi: 10.1161/01.CIR.28.4.536
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