Hypertension and the Kidney-An Overview

Eberhard Ritz, MD, FRCP, and Danilo Fliser, MD

• The kidney plays a major role in the genesis of any type of hypertension, as demonstrated by experiments which
show that hypertension can be "transplanted" when the kidney itself is transplanted. Hypertension is common in
patients with renal disease, and may occur even at normal glomerular filtration rates. The mechanisms that promote
hypertension and are involved in renal disease comprise both activation of pressor mechanisms and failure of depressor
mechanisms, the latter having been considerably less well studied. The major pressor mechanisms are an abnormal
pressure-natriuresis relationship and inappropriate activity of the renin-angiotensin system.
© 1993 by the National Kidney Foundation, Inc.

INDEX WORDS: Renal hypertension; renal salt excretion; renin-angiotensin system; medullolipins; nitric oxide.

T HE RECOGNITION that hypertension is a

feature of chronic renal disease dates back
to the seminal observations of Richard Bright, 1
who noted cardiac hypertrophy in patients who
were dying from renal failure. The kidney plays
an overriding role in the induction and mainte-
nance of any type of hypertension, even putative,
nonrenal hypertension (ie, primary, or essential,
hypertension). This has been most clearly doc-
umented by cross-transplantation experiments,
which have illustrated that hypertension can be
"transplanted" with the kidney. Rettig et al 2
demonstrated that transplantation of a genetically
"hypertensive" kidney (ie, that of a spontaneously
hypertensive rat) into a histocompatible recipient
with lower blood pressure caused a progressive
increase in blood pressure in the recipient animal.
This observation indicates that a kidney that
is genetically programmed for hypertension can
override the extrarenal blood pressure regulation
of the recipient, even though the latter is genet-
ically programmed to normotension. Such an in-
crease in blood pressure cannot be explained by
hypertension-induced damage to the vasculature
of the donor kidney, since this phenomenon also
is seen when kidneys are taken from animals that
have rigorously been kept normotensive since
birth by antihypertensive treatment.
The experimental evidence that transfer of a
genetically normotensive kidney into a hyper-
tensive recipient lowers blood pressure is less im-
pressive. This point is of considerable interest
since strong arguments can be made that certain
renal mechanisms also are involved in lowering
blood pressure.
The above observations also are relevant to
hypertension in humans. Curtis et al 3 studied
subjects with primary hypertension who had de-
veloped renal failure as a result of hypertension-
induced nephangiosclerosis. Transplantation of
a genetically "normotensive" kidney (ie, a kidney
from a normotensive donor) rendered such re-
cipients permanently normotensive without an-
tihypertensive medication despite their (pre-
sumed) genetic predisposition to hypertension.
EVIDENCE FOR RENAL DYSFUNCTION IN
GENETICALLY HYPERTENSIVE INDIVIDUALS
Following the findings from rat experiments
that hypertension can be transplanted together
with the kidney, Bianchi et al4 were the first to
demonstrate renal hemodynamic abnormalities
in normotensive offspring of hypertensive par-
ents. This issue has been taken one step further
by Montanari et al, 5 who documented renal va-
soconstriction that was responsive to the admin-
istration of calcium antagonists in such geneti-
cally prehypertensive individuals.
Moreover, Van Hooft et al 6 documented renal
vasoconstriction in normotensive offspring of
hypertensive parents, as evidenced by reduced
clearance of para-amino hippuric acid. Impaired
renal excretion of sodium was suggested by the
observation of expanded volume with (compen-
satory?) suppression of plasma renin activity
(PRA) and aldosterone. A subtle natriuretic ab-
normality in response to sodium loading in nor-
motensive offspring of hypertensive parents? has
been noted by several investigators and may con-
stitute a key renal mechanism whereby the kidney
mediates the blood pressure increase in primary
hypertension patients.
From the Department ofInternal Medicine, Ruperto-Carola
University, Heidelberg, Germany.
Address reprint requests to Eberhard Ritz, MD, FRCP, De-
partment of Internal Medicine, Division of Nephrology,
Bergheimer Strasse 58, D-6900 Heidelberg, Germany.
© 1993 by the National Kidney Foundation, Inc.
0272-6386/93/2106-3002$3.00/0

American Journal of Kidney Diseases, Vol 21, No 6, Suppl 3 (June), 1993: pp 3-9 3
4 RITZ AND FLISER

180
tients with type I diabetes and nephropathy,
higher blood pressures were found in the parents
170 Boys GIrls
of these patients. 12 Furthermore, higher rates of
Na+,Li+-countertransport (a putative marker for
160 primary hypertension) were observed in diabetic
patients with nephropathy compared with those
150 without.
c;
:I:
E
Pursuing a similar line of thought, we mea-
§.
~ 140
sured blood pressure in parents of patients with
~
~
biopsy-confirmed primary chronic glomerulo-
nephritis and parents of matched controls, ie,
i 130
visitors to the emergency department of a surgical
!
CI) clinicY As shown in Table 1, hypertension was
120
of considerably greater prevalence in the parents
of patients with glomerulonephritis, which may
110
indicate that a genetic predisposition to hyper-
tension also may increase the risk of nondiabetic
100 renal disease.

90
WHAT IS THE NORMAL BLOOD PRESSURE
At
presentatIOn
After complete
remiSSion
At
presentation
After complete
remission
FOR A PATIENT WITH A DISEASED KIDNEY?

Fig 1. Systolic blood pressure at presentation and

The rate of progression of renal failure depends
after complete remission in children with minimal change on the level of blood pressure. This has been well
glomerulonephritis. (Reprinted with permission of S. illustrated by a recent Italian study of lupus ne-
Karger AG, Basel.')
phritis,14 which indicated that renal survival was
lower in hypertensive patients compared with
CLINICAL OBSERVATIONS OF HYPERTENSION nonhypertensive patients.
IN RENAL DISEASE PATIENTS In this context, the issue of what constitutes
It is important that the renal mechanisms that "normal blood pressure" for a diseased kidney is
cause hypertension in renal disease may operate of interest. The normal range for blood pressure
even when the glomerular filtration rate (GFR) has been arbitrarily defined by the World Health
is normal. This is illustrated by the findings of Organization, which, fully aware that a consistent
Kuster et al, 8 who studied blood pressure in ne- increase is found in the risk of cardiovascular ac-
phrotic children with minimal change glomeru- cidents as blood pressure rises, chose this arbitrary
lopathy, a paradigm of renal dysfunction, despite threshold since it was felt that antihypertensive
a normal GFR and the finding of a normal glo- intervention below this level "was more likely to
merular structure using light microscopy. The cause nuisance than benefit."
blood pressure in these children was consistently However, there are several indications that
above the 95th percentile corrected for age during 140/90 mm Hg may not represent an optimal
relapse of the nephrotic syndrome and prior to
administration of steroids; during remission the Table 1. Blood Pressure Status of Parents of
blood pressure decreased in practically all of the Glomerulonephritis Patients and Parents of Controls
children (Fig I).
Parents of
Hypertension is also more prevalent in nu- Glomerulonephritis Parents of Controls
merous other types of glomerular disease, even Patients (n = 63) (n = 138)
when the GFR is normal. 9- 11 Such clinical ob-
servations suggest that the kidney may affect Hypertension' 68% 41%
Normotension 32% 59%
blood pressure by subtle mechanisms that are in-
dependent of the GFR. , Hypertension is defined as ~ 140/90 mm Hg on anti-
There may be one further complexity to the hypertensive treatment.
genesis of hypertension in renal disease. In pa- Reprinted with permisssion. '3
HYPERTENSION AND THE KIDNEY 5

%lyear
75 R",Q.85
The reasons why the diseased kidney is so
2p=02% uniquely susceptible to even minor increments
in blood pressure are undoubtedly complex. One
50 major mechanism is illustrated in Fig 3. In the
\
Mlcroalbuminuna
diseased kidney preglomerular vessels, including
the afferent arterioles, are dilated and autoregu-
25
lation is lost.' 9 ,20 This implies that a higher pro-
portion of systemic blood pressure will be trans-
125 mitted to the glomerular vascular bed, causing
. 115
glomerular capillary hypertension, which is one
. factor in the initiation and perpetuation of glo-
-25
I 1.0 merular damage.
.. To make an informed choice of antihyperten-
ProteinUria

sive medication, the pathogenic mechanisms by

which the kidney increases blood pressure in renal
.
R... O.87
20
2p=1%
mUminl
month
disease must be thoroughly understood. Although
current knowledge is still incomplete, some points
Fig 2. (Top) Relationship between increase in urinary that relate to this issue will be discussed in the
albumin excretion (UAE) rate and mean arterial pressure
during an observation period of 5 years. (Bottom) following sections.
Relationship between decreases in the GFR and mean
arterial pressure (MAP) in proteinuric diabetic patients. THE SODIUM-PRESSURE RELATIONSHIP
Re-extrapolation to the point of no increase in urinary
albumin excretion rate and no decrease in the GFR (in- Several years ago, Guyton 21 postulated that
tersection with the abscissa) yields MAPs of 95 and 105 renal mechanisms, more specifically, the natri-
mm Hg, respectively. (Reprinted with permission. 15 )
uresis-pressure relationship, are of overriding
importance for the long-term regulation of blood
pressure. Both kybemetic modeling and actual
blood pressure in the presence of renal disease.
Mogensen l5 analyzed the increment in albumin-
uria and the decrement in GFR in nephropathic
diabetic patients as a function of mean arterial
blood pressure. As shown in Fig 2, when the mean
arterial pressure-albuminuria relationship is re-
extrapolated to a zero increase in albuminuria,
the regression line intersects the abscissa at 95
mm Hg mean arterial pressure. Other observa-
tions also indicate that pressures below 140/90
mm Hg are associated with less decrement in
GFR in patients with primary chronic renal dis-
ease. 16 mmHg

These findings concur with those of Janka et ------- .... , ,

al in the Diabetic Retinopathy Study,'? who " ,
found that diabetic patients had negligible excess ....... Afferent

/
....... ....... vasodilatation
vascular risk at diastolic pressures lower than 70 '...............
mm Hg. Furthermore, Knowler et al 18 studied ...... _--------
diabetic Pima Indians and found that the risk of
retinopathy increased with rising blood pressure,
even in the normotensive range. The weight of
such evidence may force us to redefine the con- Systemic pressure Glomerular pressure

cept of "optimal" blood pressure in patients with

Fig 3. Effect of afferent (preglomerular) vasodilatation
diseased kidneys (and perhaps also in patients on transmission of systemic blood pressure into the glo-
with extrarenal pathology). merular capillary bed (glomerular hypertension).
6 RITZ AND FLiSER
120
t-----------------------t
Oi
J:
E
g
110
~ tension goes back to the classical experiments of
i 100
"~ f------------------------~
.
go-
o
~ 80
50
Urinary sodium excretion (mmol/day)
Fig 4. Relationship between urinary sodium excretion
and mean arterial pressure in controls (open circles) and
in patients with autosomal dominant polycystic kidney
disease (closed circles) on the seventh day of low (20
mmol/d) and high (200 mmol/d) sodium intake. Controls
and patients on the low sodium diet had significantly
different baseline blood pressures. In addition, the slope
of the urinary sodium-blood pressure relationship was
significantly different. (Reprinted with permission of
Current SCience. 23 )
experiments showed that activation of extrarenal
pressor mechanisms persistently failed to increase
blood pressure unless the pressure-natriuresis re-
lationship was reset to higher blood pressure
levels.
There is good evidence for sodium retention
in patients with renal failure. 22 Furthermore, even
in incipient renal failure, the pressure-natriuresis
relationship may be shifted to the right and blood
pressure may become sensitive to both salt and
volume, as shown in Fig 4. 23
It has been more difficult to provide evidence
for abnormal renal handling of sodium in subjects
with primary hypertension. In early studies, a
lowish exchangeable sodium, if anything, was
noted in patients with primary hypertension. 24
More recently, however, several investigators
have documented increased sodium sensitivity
of blood pressure in a proportion of patients with
primary hypertension 25 and even in young nor-
motensive individuals who were genetically pre-
disposed to primary hypertension. 7 The mecha-
nism(s) through which the kidney is prevented
from excreting sodium at normal pressures is not
well understood. Postulates range from abnormal
intrarenal catecholamine action 7 to ingenious
theories implying a role for a circulating inhibitor
ofNa+,K+-ATPase, 26 a theory that may be proven
or disproven in the near future, since ouabain
has been shown to be a circulating inhibitor of
Na+,K+-ATPase that can now be measured.
THE RENIN-ANGIOTENSIN SYSTEM
The recognition that renin promotes hyper-
Tigerstedt and Bergmann and the demonstration
of its release from the ischemic kidney by Gold-
blatt. However, subtle abnormalities of the renin-
angiotensin system (RAS) have been recognized
200
only recently in patients with no gross elevation
in PRA, ie, in the absence of renal artery stenosis
or other renovascular pathology.
Autosomal dominant polycystic kidney disease
(ADPKD) is a useful paradigm to illustrate how
inappropriate activity of the RAS may contribute
to blood pressure elevation in renal disease de-
spite PRA levels that are within the normal range.
Early investigators27 ,28 who studied patients with
ADPKD measured PRA levels within the normal
range and concluded that the RAS was not related
to the elevation of blood pressure. More recently,
however, higher post-captopril PRAS29 and higher
basal PRAs have been found in juvenile subjects
with ADPKD when compared with appropriate
controls, ie, patients with primary hypertension
who were matched for blood pressure. 30 This
finding points to an inappropriate activity of the
RAS, which is further supported by a comparison
of angiotensin II levels with the number of an-
giotensin II receptors on thrombocytes. 31 As
shown in Table 2, although patients with
ADPKD had substantially higher blood pressures,
angiotensin II levels, the number of angiotensin
II receptors on the platelets were not as low as
would be expected, suggesting inappropriate ac-
tivity of the RAS. Activation of the RAS also
could be demonstrated by immunostaining of the
Table 2. Inappropriate Angiotensin II Levels
in Autosomal Dominant Polycystic
Kidney Disease (ADPKD) Patients
Angiotensin II
Mean Artenal Angiotensin II Receptors
Pressure Concentration (Sites!
(mmHg) (fmol!mL) Platelet)
Low salt intake
(20 mmol/d)
ADPKD (n = 9) 107,2 ± 3,4 22.2 ± 3.8 1.5 ± 0.47
Controls (n = 9) 92.7 ± 2.7 28.1 ± 6.8 2.7 ± 0.98
High salt intake
(200 mmol/d)
ADPKD (n = 9) 111.2 ± 2.9 5.7 ± 0.6 3.4 ± 0.49
Controls (n = 9) 91.9 ± 2.5 7.9 ± 1.1 6.1 ± 2.19
Reprinted with permission of Current Science 2 •
HYPERTENSION AND THE KIDNEY
kidneys for renin. 32 The number of angiotensin
II receptors on the platelets correlates closely with
the acute pressor response to angiotensin II in-
fusion, as shown previously in our laboratory.
The potential functional relevance of inappro-
priate activation of the RAS is illustrated by the
observation that angiotensin converting enzyme
inhibition selectively increases renal plasma flow
in patients with ADPKD, but not in controls,33
suggesting angiotensin II-mediated renal cortical
vasoconstriction. Since renal vasoconstriction
alters renal sodium excretion, the two hyperten-
sinogenic phenomena (an abnormal pressure-
natriuresis relationship and inappropriate acti-
vation of the RAS) may be interrelated and may
mutually amplify each other.
A wide range of PRA values is found in indi-
viduals with primary hypertension, although the
median PRA lies well within the normal range.
More recently, intemephron heterogeneity with
respect to the activity of the renal renin system
has been suggested by Laragh. 34 This novel con-
cept also may provide a conceptual framework
to accommodate the co-existence of ischemic and
overperfused nephrons, as is frequently found in
chronic renal disease.
Animal experiments provide further evidence
for an important role of the renal renin system
in the long-term regulation of blood pressure in
situations in which renal disease is not present.
In the conscious, chronically instrumented dog,
long-term regulation of blood pressure correlated
strongly with the renal autoregulatory threshold
for renin secretion, ie, the critical level of mean
pressure in the renal artery below which renin
secretion was stimulated. 35
More definite evidence for overtly inappro-
priate activity of the RAS has been obtained in
patients with renal failure. 22 ,36 To correctly in-
terpret PRA, it must be remembered that a re-
ciprocal relationship exists between renin secre-
tion and arterial pressure so that PRA should be
close to zero in the hypertensive renal patient.
Apart from blood pressure, an expanded sodium
space also will suppress the RAS. In the study by
Weidmann et al,36 the relationship between ex-
changeable sodium and PRA was compared in
normal subjects and in normotensive and hy-
pertensive uremic subjects. It was found that at
any given level of exchangeable sodium, PRA was
higher in uremic subjects, and more so in hy-
7
pertensive than in normotensive patients. This
indicates that PRA is too high relative to sodium
and to blood pressure.
The activity of the RAS depends on the type
of underlying renal disease, being particularly
high in patients with nephangiosclerosis and glo-
merulonephritis. 36 It is excessive in a minority of
uremic patients whose blood pressure does not
respond to loss of volume, and it is these patients
who in the past required bilateral nephrectomy3?
and who today benefit particularly from angio-
tensin converting enzyme inhibitors.
THE SYMPATHETIC NERVOUS SYSTEM
The kidney is the origin of, and the target for,
sympathetic efferent and afferent nerve traffic. 33
Afferent nerve traffic is stimulated by intrarenal
mechanoreceptors and chemoreceptors, while ef-
ferent sympathetic nerve traffic modulates renal
renin release and renal vascular resistance and
directly modulates tubular transport of sodium.
A role for the sympathetic nervous system in the
genesis of blood pressure elevation in models of
renal hypertension is suggested by observations
that selective renal denervation abrogated or de-
layed the onset of blood pressure elevation in dif-
ferent models of renal hypertension. 38
In the past, the sympathetic nervous system
was not thought to be a major contributor to the
genesis of renal hypertension. However, this view
is now known to be incorrect. Norepinephrine
levels are elevated in patients with renal failure,
but this finding is difficult to interpret because
re-uptake of norepinephrine is diminished. Fur-
thermore, the increase in vascular resistance in
response to norepinephrine is impaired in the
vasculature of uremic animals. 39 Nevertheless,
sympathetic overactivity appears to playa major
role in the maintenance of elevated blood pres-
sure. Schohn et al40 found that sympathetic
blockade with debrisoquine dramatically reduced
blood pressure in hypertensive uremic patients.
McGrath et al41 carried this one step further and
studied the effect of total autonomic blockade
using atropine and beta- and alpha-adrenoceptor
blockers. Total autonomic blockade dramatically
lowered blood pressure and total peripheral re-
sistance in hypertensive patients on dialysis, ir-
respective of whether they were on a low- or high-
salt diet. The relationship between sympathetic
overactivity and increased blood pressure gains
8 RITZ AND FLiSER
further credence from the microneurographic
studies of Victor et al,42 who demonstrated in-
creased efferent sympathetic nerve traffic in ure-
mic patients.
THE CIRCULATING INHIBITORS OF
NITRIC OXIDE SYNTHESIS
An entirely new perspective was opened up by
the findings of Vallance et al,43 who identified a
derivative of L-arginine, asymmetric dimethylar-
ginine, in the circulation of uremic animals. This
compound competitively inhibits the synthesis
of nitric oxide from L-arginine and, when given
to guinea pigs, increased blood pressure dose de-
pendently and over prolonged periods of time.
Cumulation of such hypertension-promoting
inhibitors of endothelium-derived relaxing factor
may explain the known prevalence and severity
of hypertension in end-stage renal failure patients
and also may explain why prolonged duration of
dialysis sessions will keep most patients normo-
tensive, even if they do not receive antihyperten-
sive medication. 44
THE RENAL VASODEPRESSOR FACTORS
The genesis of hypertension in renal disease
usually is interpreted in terms of renal activation
of pressor factors. However, this concept may be
incomplete. Loss of renal depressor mechanisms
and failure to reduce blood pressure may consti-
tute a potentially important pathogenetic aspect
of renal hypertension. Blood pressure-lowering
lipid substances can be extracted from the inter-
stitial cells of the renal medulla,45 but, until re-
cently, it was not possible to confirm whether
such substances affected blood pressure under
physiologic circumstances.
In elegant cross-perfusion experiments, Karls-
tram et al varied the perfusion pressure of the
isolated perfused rat kidney within the range of
pressures occurring in vivo and noted a dose-de-
pendent decrease in blood pressure and natri-
uresis in the recipient rat. 46 ,47 This implies that
depressor substances, presumably medullolipins,
are released from the kidney with increasing renal
perfusion pressures. The concept of renoprival
hypertension48 (ie, hypertension as a consequence
ofloss of renal function) had found disfavor after
it was shown that anephric individuals were ren-
dered normotensive by subtraction of volume via
ultrafiltration. Nevertheless, in view of the above
experiments, one would anticipate hypertension
in diseases that destroy the renal medulla. Indeed,
in analgesic abusers, who suffer from papillary
destruction, we have noted a high prevalence of
hypertension (over 80%), even when the serum
creatinine level was below 1.1 mg/dL. 49
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