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Drugs 35 (Suppl, 5): 62-71 (1988)
0012-6667/88/0500-0062/$5.00/0© ADIS Press LimitedAll rights reserved .
Renal Protective Effect of Long TermAntihypertensive Therapy with Enalapril
John H. Bauer and Garry P. ReamsHypertension Section, Division of Nephrology, Department of Medicine, University ofMissouri School of Medicine, Columbia
Summary This review focuses on recent human studies with the angiotensin-converting enzyme(ACE) inhibitor enalapril, prescribed either alone or in combination with a diuretic, topatients with essential hypertension and to patients with hypertension associated withmoderate to severe renal parenchymal disease. Data suggest that enalapril therapy mayprovide a renal protective effect. In addition to lowering and controlling systemic arterialblood pressure, enalapril therapy is associated with stabilisation of, and/or improvementin effective renal plasma flow, glomerular filtration rate (GFR) and urinary protein excretion. Such renal protective effects are probably mediated by normalisation ofboth thesystemic arterial blood pressure and intraglomerular capillary hydraulic pressure, and byan increase in the glomerular ultrafiltration coefficient. Drug therapy enabling control ofboth systemic and glomerular hypertension may prevent hypertensive renal end-organdamage and attenuate the natural progression of renal parenchymal disease.
For patients with essential hypertension, andpatients with hypertension associated with moderate to severe renal parenchymal disease, drugtherapy which can attenuate the effects of angiotensin II on the systemic and intrarenal vasculature (table I) has the potential to normalise bothsystemic arterial pressure and glomerular capillaryhydraulic pressure. Such therapy may improve effective renal plasma flow, lower renal vascular resistance, and decrease urinary protein excretion.Furthermore, by attenuating the effects of angiotensin II on the mesangium, (i.e. by increasing theultrafiltration coefficient), such treatment may stabilise or improve the glomerular filtration rate(GFR).
This review focuses on recent human studieswith the angiotensin-converting enzyme (ACE) in-
hibitor enalapril, given as monotherapy or in combination with a diuretic to patients with essentialhypertension and to patients with hypertension associated with moderate to severe renal parenchymal disease. The data suggestthat enalapril therapymay convey a renal protective effect, since in addition to lowering and controlling systemic arterialblood pressure, renal function is stabilised or improved.
We suggestthat this renal protection results fromstrict control of both systemic arterial blood pressure and intraglomerular capillary hydraulic pressure. It remains to be determined whether the renalprotective effect of enalapril is drug specific andrelated to the high concentration of enalaprilachieved in renal tissue, or whether it is a propertyof all ACE inhibitors.
Renal Protect ive Effect of Enalapril
Table I. Direct actions of angiotensin II within the kidney
63
Vascular endothelium
Preferential constriction of the efferent postglomerular arterioles, which increases the filtration fract ion and results in:proximal tubular sodium and water reabsorptionat low perfusion pressures, regulation (preservation) of glomerular filtration rate
enhanced transglomeru lar passage of albumin
Tubular epithelium
Direct effect on the renal tubular transport of sodium and water resulting in:sodium reabsorption (antinatriuresis)water reabsorpt ion (antidiuresis)
Mesangial cells
Direct effect on the mesangial cells, resulting in:contraction of the mesangium, and reduction, therefore, in the ultrafiltration coefficient, and in the glomerular filtration rate
increased mesangial uptake of macromolecules and disruption of macromolecular clearance; trapping may precipitate mesangialinjury which leads to sclerosis
Juxtaglomerular cells
Direct inhibition of renin release (short-loop, negative feedback mechanism)
Interstitial cells
Direct stimulation and biosynthesis of vasodilatory prostaglandin
1. Renal Protective Effects of Enalapril inEssential Hypertension1.I Study Design
23 patients with essential hypertension were included in this prospective study, and for 3 yearsserial assessment of renal function during eitherenalapril monotherapy (n = 8) or enalapril-hydrochlorothiazide therapy (n = 15) was made. Thesepatients were from a group of 39 patients originallyincluded in a study with a double-blind, randomised protocol designed to compare their blood pressure and renal function lresponses to enalaprilmonotherapy, enalapril-hydrochlorothiazide combination therapy , or hydrochlorothiazide monotherapy (Bauer & Jones 1984). After 8 weeks' treatment, patients unresponsive to either monotherapywere placed on the combination therapy , and at Iyear 9 patients were on 'enalapril monotherapy(mean dose 22 rug/day), 21 were on combinationtherapy (mean doses;' enalapril 21 rug/day andhydrochlorothiazide 52 rug/day), and 4 were onhydrochlorothiazide monotherapy (mean dose 88mg/day) [Bauer & Gaddy, 1985]. Patients whoseblood pressure was successfully controlled on either
enalapril monotherapy or enalapril-h ydrochlorothiazide combination therapy were continued in theprotocol. AI! 9 patients randomised to enalaprilmonotherapy (mean dose 17.7 rug/day), and 20 of21 patients on combination therapy (mean doses,enalapril 20.5 mg/day and hydrochlorothiazide 51mg/day), were assessed for renal function for 2 years(Reams & Bauer 1986a). Eight of the 9 patientsrandomised to enalapril monotherapy (mean dose17.5 mg/day), and 15 of the 21 on combinationtherapy (mean doses, enalapril 20.7 rug/day andhydrochlorothiazide 51.7 mg/day), were assessedfor renal function for 3 years (Bauer et al. 1987a).
1.2 Results
Systolic and diastolic arterial blood pressure(first and fifth phase) were controlled well in boththe recumbent and upright positions (table II).GFR, assessed by serum creatinine concentration,creatinine clearance or inulin clearance, was unchanged throughout the study when compared withthe pretreatment (placebo) assessment (table III).There was a sustained 17% increase in effectiverenal plasma flow. Mean filtration fraction and ur-
Renal Protective Effect of Enalapril
Table II. Response of blood pressure (mean ± SO, n =23) to enalapri l therapy in essential hypertension
Placebo Year 1 Year 2 Year 3
Recumbentsystol ic pressure (mm Hg) 156 ± 14 123 ± 10' 120 ± 10" 127 ± 20"diastolic pressure (mm Hg) 104 ± 4 81 ± 8" 80 ± 8" 83 ± 6"
Upright
systolic pressure (mm Hg) 155 ± 14 120 ± 10" 115 ± 9" 118 ± 16"diasto lic pressure (mm Hg) 106 ± 6 82 ± 6" 80 ± 7" 82 ± 6"
, = P < 0.01, " = P < 0.0005 compared with placebo .
Table III. Response of renal funct ion (mean ± SO, n = 23) to enalapril therapy in essential hypertension
Placebo Year 1 Year 2 Year 3
Scr (mg/dl) 1.38 ± 0.18 1.30 ± 0.20 1.25 ± 0.18" 1.24 ± 0.17"
Ccra 91 ± 23 94 ± 21 93 ± 17 93 ± 20
C inulina 84 ± 30 95 ± 24 95 ± 25 93 ± 26
Cpaha 326' ± 107 388 ± 129" (n = 22) 388 ± 104 (n = 22) 398 ± 73'
Cinulin/Cpah (%) 26.1 ± 6.0 26.3 ± 7.9 (n = 22) 25.4 ± 4.8 (n = 22) 24.6 ± 6.3
U proteinb 0.06 ± 0.06 0.05 ± 0.06 0.04 ± 0.01 (n = 21) 0.08 ± 0.12
64
a ml/min/1.73m2•
b gIg creatin ine.Abbreviations : Scr = serum creatinine ; Ccr = creat inine clearance ; Cinulin = inulin clearance ; Cpah = para-aminohippurate clearance ;
Cinulin/Cpah = filtration fract ion; UpI'D'.in = 24-hour urinary protein excretion. ' = p < 0.01, " = P < 0.001 compared with placebo.
inary protein excretion were also unchanged. 12 ofthe 23 patients had moderately impaired renalfunction (inulin clearance ~ 80 ml/min/1.73m2)
before starting active drug therapy, and after thefirst year a 50% increase in their inulin clearanceand a 39% increase in their effective renal plasmaflow was observed (table IV). After 3 years' treatment inulin and para-aminohippurate clearanceswere 33 and 47% higher, respectively, than afterplacebo therapy. The less sensitive markers of renalfunction, serum creatinine concentration and creatinine clearance, demonstrated qualitatively similar mean changes. In these patients, mean filtration fraction and urinary protein excretion wereunchanged. II patients who entered the study withnormal renal function (inulin clearance > 80 milmin/1.73m2) demonstrated no change in their indices of renal function (table V).
Of the 7 patients withdrawn from the study during the second and third years, 5 experienced an
intercurrent illness (ischaemic heart disease requiring the addition of a {j-blocker), I died of ischaemic heart disease, and I was withdrawn because of alcoholism. None of these patients hadexperienced a deterioration in renal function at thetime of their exclusion from the study. All had normal levels of glomerular filtration; the average inulin clearancebefore withdrawal from the study was97 ml/min/1.73m2•
1.3 Discussion
The data demonstrate that long term enalaprilmonotherapy or enalapril-hydrochlorothiazidecombination therapy lowered and controlled systemic arterial blood pressure and stabilised or improved GFR, effective renal plasma flow and urinary protein excretion. The level of glomerularfiltration sustained in these patients, with this therapeutic modality, is similar to that observed in age-
Renal Protective Effect of Enalapril
matched normotensive controls (Baueret al. 1982a).The maintenance of a relatively high filtration fraction, from 24.6 to 26.3%, suggests that the improvement in GFR was disproportionately greaterthan the respective increase in effective renalplasma flow. A normal filtration fraction in ourlaboratory averages 21 to 22%(Bauer et al. 1982a).
Patients with moderately impaired renal function (inulin clearance ~ 80 ml/min/L'Bm? but ~40 ml/min/1.73m2) demonstrated an initial markedincrease in both inulin and para-aminohippurateclearances. Increases in renal filtration and perfusion were generally sustained after 3 years' treatment. We suggest that the above improvements in
65
renal function resulted from strict control of bothsystemic arterial blood pressure and intraglomerular capillary hydraulic pressure. Interruption ofthe intrarenal renin-angiotensin system shouldmitigate the effects of angiotensin II on the glomerular mesangium (sustaining and/or increasingthe ultrafiltration coefficient),and also mitigate theeffects of angiotensin II on efferent arteriolar resistance (decreasing renal vascular resistance andglomerular capillary hydraulic pressure) [Bauer1984; Bauer & Reams 1986].
The natural course of untreated essential hypertension is characterised by progressive impairmentof renal function (Lindeman et al. 1984; Moyer et
Table IV. Response of renal function (mean ± SO, n == 12) to enalapriltherapy in patients with initial GFR < 80 ml/min/1 .73m2
Sysl./diasl. BP (mm Hg)
Sc, (mg/dl)Cera
Cinulin
Cpaha
Cinulin/Cpah(%)
Uproteinb
Placebo
154 ± 12/104 ± 41.38 ± 0.2081 ± 2660 ± 14
256 ± 7223.9 ± 3.9
0.08 ± 0.07
Year 1
119 ± 9"""/80 ± 9"""1.35 ± 0.2190 ± 2391 ± 19"""357 ± 100""" (n == 11)
26.7 ± 5.9 (n == 11)
0.07 ± 0.08
Year 2
119 ± 9"""/82 ± 8"""1.27 ± 0.20"
87 ± 1286 ± 13"""363 ± 72""" (n == 11)
25.0 ± 2.5 (n == 11)
0.05 ± 0.025
Year 3
126 ± 19"""/84 ± 6"""1.23 ± 0.20"85 ± 1780 ± 20""376 ± 81"""
21.9 ± 5.6
0.13 ± 0.16
a ml/min/1 .73m2•
b gIg creat inine.Abbreviations: BP == blood pressure (systolic/diastolic in recumbent position); Sc, == serum creat inine; Cc, == creatin ine clearance;
Cinulin == inulin clearance; Cpah == para-aminoh ippurate clearance; Cinulin,Cpah == filtration fraction; Up,olein == 24-hour urinary ·proteinexcretion; GFR == glomerular filtration rate. " == p < 0.02, "" == P < O.Q1 , """ == P < 0.001 compared with placebo .
Table V. Response of renal function (mean ± SO, n == 11) to enalapriltherapy in patients with initial GFR > 80 ml/min/1.73m2
Placebo Year 1 Year 2 Year 3
SySI./diasl. BP (mm Hg) 158 ± 15/105 ± 4 128 ± 11""/83 ± 6"" 120 ± 10""/79 ± 8"" 128 ± 21"/81 ± 2""
Sc, (mg/dl) 1.38 ± 0.15 1.25 ± 0.18" 1.23 ± 0.16" 1.25 ± 0.15
Cc,a 102 ± 12 99 ± 18 99 ± 19 103 ± 20
C inulina 111 ± 17 100 ± 28 105 ± 31 106 ± 26
Cpaha 402 ± 85 420 ± 151 413 ± 127 388 ± 66
Cinulin,Cpah(%) 28.6 ± 7.1 25.6 ± 9.9 26.1 ± 6.4 27.4 ± 6.0
Uproteinb 0.04 ± 0.03 0.03 ± 0.02 0.03 ± 0.01 0.03 ± 0.03
a ml/min/1.73m2•
b gIg creatinine .Abbreviations: BP == blood pressure (systolic/diastolic in recumbent position) ; Sc, == serum creat inine; Cc, == creatinine clearance;
Cinulin == inulin clearance ; Cpah == para-amino hippurate clearance; Cinulin/Cpah == filtration fraction ; Up,otein == 24-hour urinary proteinexcretion; GFR == glomerular filtration rate. " == p < 0.01, "" == P < 0.001 compared with placebo.
Tab
leV
I.C
ompa
rati
veef
fect
sof
antih
yper
tens
ive
drug
ther
apy
onre
nalf
unct
ion
ines
sen
tialh
yper
tens
ion"
:;.;:l
(l) i:l l'>
Tre
atm
ent
SU
bjec
tsD
urat
ion
Dos
age
Mea
nar
teria
lpr
essu
re(m
mH
g)G
FR
byC
;nuh
n(m
l/min
)E
RP
Fby
Cpa
r(m
l/min
)R
emar
ks- '"t:
I(n
umbe
r)(w
eeks
)(m
g)a
(ra
nge)
cont
rol
drug
cha
nge
cont
rol
dru
gch
ange
cont
rol
drug
chan
ge<>
(%)
(%)
(%)
::l. '<' (l)
Mon
olh
era
py
(indi
vidu
aldr
ug)
ttl
Diu
reti
cs~
hyd
roch
loro
thia
zide
124
50-1
0011
710
6-9
7880
+2
336
336
0no
chan
gein
GF
R/
::l.(B
auer
&B
roo
ks19
79)
ER
PF
0 -,h
ydro
chlo
roth
iazi
de15
850
-100
121
104
-13
8484
033
131
8-4
ttl
(Bau
er
&Jo
nes
1984
)i:l ll' E;"
/I-B
lock
ers
'0
beta
xolo
l(R
eam
set
al.
1987
)13
3210
-40
118
105
-11
9990
-938
63
29-1
42:
nado
lol
(Bau
er
etal
.19
87b)
1212
40-1
6011
110
5-
596
89-7
365
328
-10
mild
decr
ease
inG
FR
/
ER
PF
pro
pra
no
lol
(Bau
er19
83a)
1424
80-3
2011
297
-13
8577
-8
361
310
-14
Ce
ntra
la2
-adr
ener
gic
agon
ists
guan
aben
z(B
auer
1983
b)17
248-
6411
210
0-
1184
69-1
836
930
6-
17m
oder
ate
decr
ease
in
GF
R/E
RP
F
Per
iphe
rala
,-a
dren
ergi
can
tago
nist
spr
azo
sin
(Bau
eret
al.
1964
)12
242-
2010
898
-985
100
+18
371
356
-4m
od
erat
ein
crea
sein
GF
R
Cal
cium
anta
goni
sts
amlo
dip
ine
(Rea
ms
etal
.19
62
.5-1
011
810
4-1
291
103
+13
377
449
+19
mo
der
ate
incr
ease
in
inpr
ess)
GF
R/E
RP
F
dilt
iaze
m:
(Sun
derr
ajan
etal
.19
86)
1G
FR
>80
ml/m
in/1
.73m
210
824
0-48
012
41
11-1
011
693
-20
405
350
-14
mod
era
tede
cre
ase
in
GF
R/E
RP
F
2G
FR
..80
ml/m
in/1
.73m
28
824
0-48
011
910
5-1
260
89+
4825
033
9+
36m
arke
din
crea
sein
GF
R/E
RP
F
AC
Ein
hib
itors
enal
april
(Ba
uer
&G
addy
1985
)
1G
FR
>80
ml/m
in/1
.73m
26
810
-40
122
94-
2312
910
4-1
950
444
6-1
2m
oder
ate
decr
ease
in
GF
R/E
RP
F
2G
FR
..80
ml/m
in/1
.73m
210
810
-40
123
103
-16
5769
+21
249
329
+32
mar
ked
incr
ease
in
GF
R/E
RP
F
0-.
0-.
;:0C
ombi
natio
nth
erap
ies
'"~ ~h
ydro
chlo
roth
iazi
de
+12
1250
-100
117
99-
1578
76-3
336
339
+1
noch
ange
InG
FR
/-
pro
pra
nolo
l80
-360
ER
PF
.." .., 0
(Bau
er
&B
roo
ks19
79)
"~h
ydro
chlo
roth
iazi
de
+25
-100
<'e
nala
pril
10-4
0'" rn
1G
FR
>8
0m
l/m
ln/l
.73m
29
9612
392
-25
107
104
-340
341
9-4
noch
ange
inG
FR
/~
ER
PF
~2
GF
R'"
80
ml/m
in/l
.73m
211
96
120
93-
2362
86
+3
927
337
7+
38
mar
ked
incr
ease
din
0 -,(R
eam
s&
Bau
er19
86b
)G
FR
/ER
PF
rn ~m
eto
lazo
ne
+15
262.
5-1
012
710
0-
2191
80-1
229
125
0-1
4m
od
erat
ed
ecre
ase
in~ 60
beta
xolo
l/ate
no
lol
+20
/50-
200
GF
R/E
RP
F'0
min
oxi
dil
5-20
2:(R
eam
s&
Bau
er.
unpu
blis
he
d)
aE
xper
ienc
ein
Re
nal
Dia
gno
stic
Lab
orat
ory,
Hyp
erte
nsi
onS
ectio
n,
Uni
vers
ityo
fM
isso
uri
-Co
lum
bia
.A
bb
revi
atio
ns:
GF
R=
glo
mer
ular
filtr
atio
nra
te;
ER
PF
=ef
fect
ive
rena
lpl
asm
aflo
w;
Cin
ulin
=in
ulin
clea
ranc
e;
Cp
ah
=pa
ra-a
min
ohip
pura
tecl
eara
nce
;A
CE
=an
gio
tens
in
con
vert
ing
enzy
me
.0
\ ....,
Renal Protective Effect of Enalapril
al. 1958). Effective, long term antihypertensivetherapy may oppose this tendency . The renal effects of most classes of antihypertensive drugs currently prescribed for the treatment of essentialhypertension are shown in table VI. It is clear fromthese studies that pharmacological control of systemic arterial blood pressure does not adversely affect renal function , with the potential exceptionsbeing {1-adrenergic antagonism, central £¥radrenergic agonism , and triple drug therapy with metolazone, a {1-blocker and minoxidil. Usually , GFRand effective renal plasma flow are sustained atlevels recorded after a placebo run-in period. However, with the exception ofcalcium antagonists andthe ACE inhibitors, none of these drug classes produced and sustained a clinically significant increase in GFR and effective renal plasma flow. Onlythe ACE inhibitors and the calcium antagonists(which also attenuate the intrarenal effects ofangiotensin II) appear to reverse renal function andhaemodynamic abnormalities found in patientswith essential hypertension.
Of some concern may be the decrease in GFRpreviously observed in patients with essentialhypertension and a normal GFR (inulin clearance~ 80 ml/min/1.73m2) who were prescribed eitheran ACE inhibitor or a calcium antagonist (tableVI). This could result from a reduction in intraglomerular capillary hydraulic pressure caused byreducing efferent arteriolar vascular resistance inthe absence of a compensatory increase in the glomerular ultrafiltration coefficient. Since renal vascular abnormalities precede changes in the GFR inpatients with essential hypertension and producethe characteristic rise in the filtration fraction(Bauer et al. 1982a), it is not surprising that thepredominant effect of ACE inhibitor therapy inpatients with normal glomerular function is on therenal vasculature, and not on the glomerular mesangium. Importantly, GFR is usually not reducedto abnormal levels (inulin clearance < 80 ml/min/1.73m2), and the addition of hydrochlorothiazideattenuates this effect. The observed changes in inulin clearance are generally not detectable by theless sensitive creatinine clearance methodologies(Bauer et al. 1982b).
68
2. Renal Protective Effects of Enalapril inHypertension Associated with Moderate toSevere Renal Parenchymal Disease2.1 Study Design
The short term renal response to enalapriltherapy was assessed in 9 patients with hypertension associated with moderate to severe renal parenchymal disease (Reams & Bauer 1986a). Fourpatients had hypertensive nephrosclerosis, and 1each had polycystic kidney disease, focal glomerulosclerosis , hereditary nephritis, glomerulonephritis of unknown cause, and diabetic nephropathy. Baseline studies were performed after a briefplacebo run-in period (1 to 3 days), and after 2months of enalapril therapy (mean dose 30.5 mg/day). Three patients required the addition of frusemide (mean dose 66.6 mg/day) to achieve bloodpressure control. Five of the 9 patients were againstudied after an additional 6 months of enalapriltherapy.
2.2 Results
Systolic and diastolic blood pressure (first andfifth phase) were well controlled in both the recumbent and upright positions (table VII). GFR,assessed by serum creatinine concentration, creatinine clearance or inulin clearance, was maintained throughout the study compared with theplacebo run-in assessment (table VIII). However,there was a sustained 22%increase in effective renalplasma flow, which resulted in a sustained decreasein the filtration fraction . Urinary protection excretion was decreased markedly (-45%). Similar results have been reported by Opsahl et al. (1987).
2.3 Discussion
We suggest that the preservation of glomerularfiltration, the increase in renal perfusion, and thedecrease in urinary protein excretion resulted fromstrict control of both systemic arterial blood pressure and intraglomerular capillary hydraulic pressure. Interruption of the intrarenal renin-angiotensin system should . attenuate the effects of
Renal Protective Effect of Enalapril
Table VII. Response of blood pressure (mean ± SEM) to en-
alapril therapy in renal parenchymal disease
Placebo 2 months 6 months
n=9 n=9 n = 5
(n = 5) (n = 5)
Recumbent
Systolic 154 ± 8 137 ± 9"
(mmHg) (141 ± 8) (131 ± 8) 130 ± 8'
Diastolic 97 ± 2 86 ± 3'"
(mmHg) (93 ± 2) (85 ± 1') 81 ± 3'
Upright
Systolic 151 ± 8 130 ± 8'"
(mmHg) (144 ± 9) (128 ± 13') 129 ± 10'
Diastolic 95 ± 3 83 ± 2"
(mmHg) (91 ± 3) (83 ± 3) 84 ± 4'
, = p < 0.05; " = P < 0.015, '" = P < 0.01 compared with
placebo.
angiotensin II on the glomerular mesangium (andthus sustain the ultrafiltration coefficient), andshould also attenuate the effects of angiotensin IIon efferent arteriolar resistance (and decrease glomerular capillary hydraulic pressure). The decreasein the filtration fraction , which results from efferent arteriolar dilatation, should decrease the con-
69
centration of plasma protein along the length of theglomerular capillary, and decrease the transglomerular passage of protein because of the lower concentration gradient for diffusion and the lower concentration of protein in the convected fluid (Bohreret al. 1977). Inhibition of intrarenal angiotensin IIshould also decrease the mesangial uptake ofmacromolecules, reducing the transglomerular passage of albumin (Eisenbach et al. 1975; Keane &Raij 1985; Raij & Keane 1985; Stein et al. 1983).
The natural course of untreated hypertension inrenal parenchymal disease is characterised by progressive impairment of renal function to end-stagedisease (Branca et al. 1983; Lindeman et al. 1984;Moyer et al. 1958). The transmission of systemicpressure to the vasodilated glomerular capillarynetwork may be the most important mechanism inthe progression of renal disease in patients withhypertension. Effective long term antihypertensivetherapy may oppose this tendency, although recentexperimental evidence suggests that reduction ofsystemic arterial blood pressure alone does notprotect the impaired kidney; glomerular capillaryhydraulic pressure must also be reduced to protectthe glomeruli at risk of glomerular sclerosis (Anderson et al. 1985, 1986).
Traditional antihypertensive treatment of
Table VIII. Response of renal function (mean ± SEM) to enalapril therapy in renal parenchymal disease
Placebo 2 months 6 monthsn = 9 (n = 5) n = 9 (n = 5) n = 5
s; 3.2 ± 0.5 3.3 ± 0.6
(mg/dl) (4.1 ± 0.7) (4.3 ± 0.9) 4.4 ± 1.1c; 35 ± 4 37 ± 6
(ml/min/l.73m2) (27 ± 4) (28 ± 6) 28 ± 9
Cinulin 27 ± 5 29 ± 6(ml/min/l .73m2) (17 ± 3) (18 ± 4) 18 + 5
C pah 105 ± 12 128 ± 13"
(ml/min/l.73m2) (82 ± 14) (106 ± 17) 106 ± 30
Cinulin/Cpah 25.7 ± 2.9 21.8 ± 3.3'(%) (22.1 ± 3.3) (16.9 ± 2.1') 17.7 ± 2.3
Uprote in 1.07 ± 0.44 0.59 ± 0.30'"(g/g creatinine) (0.92 ± 0.36) (0.41 ± 0.19') 0.38 ± 0.17"
Abbreviations: So< = serum creatinine; C cr = creatinine clearance; Cinulin = inulin clearance; C pah = para-aminohippurate clearance;
Cinu lin/Cpah = filtration fraction ; Uprotein = 24-hour urinary protein excretion.
, = p < 0.05, " = P < 0.02, '" = P < 0.0015 compared with placebo.
Renal Protective Effect of Enalapril
patients with renal disease has focused on the volume and renin components of the blood pressureequation (Ulvila et al. 1972; Vertes et al. 1969).Because of abnormalities in sodium homeostasis,salt restriction and diuretics are frequently selectedas first-step therapy. Since most patients with renaldisease have an increase in their plasma volume,exchangeable sodium , and/or extracellular fluidspace (Beretta-Piccoli et al. 1976; Tarazi et al. 1970),and most classes of antihypertensive agents do notwork well in the presence of volume expansion(Finnerty et al. 1970), salt restriction and diuretictherapy have been logical and effective ways ofcontrolling systemic hypertension.
In addition, the treatment of patients with renaldisease has largely adhered to the concept ofstepped-care therapy, which usually mimics tripledrug therapy (i.e. diuretic, (j-blocker and vasodilator) for the more resistant forms of systemichypertension (Zacest et al. 1972). This approachhas been extremely effective; bilateral nephrectomy for the control of resistant-refractory systemic hypertension is no longer used. However, theeffect of these therapies on the progression of renaldisease has not been well defined. In spite of theability to control systemic hypertension in patientswith renal disease, these patients may ultimatelydie or require dialysis or transplantation. This situation has generated a number of dietary intervention trials to assess the effect of a restriction ofprotein and/or phosphate on the progression ofrenal disease.
Given our present knowledge, the use of diuretics and vasodilators as sole therapy for thetreatment of hypertension associated with renaldisease is questionable , since both stimulate therenin-angiotensin system. Drug mediated elevationof intrarenal angiotensin II has the potential tovasoconstrict the efferent pressures even thoughsystemic arterial blood pressure is reduced. Indeed,it has been demonstrated experimentally thattriple-drug therapy, with a diuretic, reserpine andhydralazine, does not reduce glomerular capillaryhydraulic pressure even though it produces a significant drop in systemic blood pressure (Andersonet al. 1986). The net clinical result is that glomer-
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ular injury and proteinuria are not reduced. Drugmediated elevation of angiotensin II also has thepotential to compromise salt and water homeostasis, glomerular filtration, and the transglomerularpassage of albumin.
3. Conclusions
The future approach toward antihypertensivetherapy in patients with renal disease should be directed not only at lowering systemic arterial bloodpressure, but also at lowering intraglomerular pressure. This appears to require pharmacological interruption of the renal renin-angiotensin system.ACE inhibitors may be the drugs to achieve thisgoal. Because these drugs are renally excreted, theybecome more cost effective (i.e. a lower dosage required) as renal function deteriorates, and their lowside effect profile (especially those with a nonsultbydryl structure) makes them particularly attractive. However, the use of {j-blockers (withoutintrinsic sympathomimetic activity) and/or calcium antagonists may also prove beneficial.
It is important to stress that the renal tissue responses to ACE inhibitor therapy may be drug, notclass, specific. Several recent reports suggest thatthe angiotensin-converting enzyme concentrationin regional tissue beds undergoes differential responses to ACE inhibitors, compared with theirrelatively uniform effect on circulating (serum)angiotensin-converting enzyme (Cohen & Kurz1982;Unger et al. 1982, 1984, 1985). Furthermore,renal tissue angiotensin-converting enzyme, ratherthan its serum counterpart, may be the crucial determinant in the long term renal vasculature and/or mesangial response to ACE inhibitor therapy.The ester prodrug enalapril has a high affinity forrenal tissue and undergoes intrarenal de-esterification (hydrolysis) to its active diacid compound,enalaprilic acid. Enalaprilic acid is a particularlypotent renal ACE inhibitor with a prolonged duration of activity. Clearly, clinical trials are now required to determine the long term clinical importance and drug specificity of the renal protectiveeffect exhibited by the ACE inhibitors .
Renal Protective Effect of Enalapril
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Author's address: Dr JohnH. Bauer, Hypertension Section - N403,University of Missouri Health Sciences Center, One HospitalDrive, Columbia, MO 65212 (USA).