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Proteinuria in renovascular hypertension and the effects of renal angioplasty
Proteinuriain RenovascularHypertensionand the Effects of RenalAngioplasty MARC S. ZIMBLER, THOMAS G. PICKERING, MD, DPhil, THOMAS A. SOS, MD, and JOHN H. LARAGH, MD
with serum creatinlne level, and in 26% ot the patients wlth renovascular hypertension, proteinuria was present despite a normal creatinine level. Renal angtoplasty produced a signlticant dlminution in proteinurla when it resulted In a cure of the hypertension, but no diminution was achieved it blood pressure did not decrease. (Am J Cardlol 1987;59:406-408)
In 46 patients with renovascular hypertension who underwent renal angioplasty, proteinuria (more than 150 mg/24 hours) was more pronounced than in patients with essential hypertension. The hl9hest levels were seen in patients in whom 1 renal artery was totally occluded. There was no dltterence between patients with unilateral vs bilateral renal artery stenosis. Proteinuria could not be correlated
R
enovascular hypertension is the most common form of curable systemic hypertension, but it is often undiagnosed because of the lack of a suitable screening test. Several studies show that proteinuria may be a characteristic finding in renovascular hypertension,l-3 and that it may diminish after successful surgery.4s5 Excessive renin levels have been suggested as the underlying cause. 4r5 The present study explores further the relation between renovascular hypertension and proteinuria, and determines whether renal angioplasty diminishes proteinuria.
were classified as cured, improved or failed using criteria described previously.6 The criteria were similar to those of the U.S. Cooperative Study of Renovascular Hypertension.7 The degree of proteinuria in these patients was compared with that in patients with essential hypertension, who were classified into 3 renin subgroups (high, normal and low] according to a reninsodium nomogram.8 For this study, only patients in the high- and low-renin subgroups were included. Most of the patients with renovascular hypertension were taking antihypertensive medications, whereas all the patients with essential hypertension had stopped taking medications for at least 2 weeks. Patients who at any time had been treated with captopril were excluded from the study. Patients with renovascular hypertension were separated into 5 groups according to whether there were stenoses of 1 or both renal arteries, whether 1 renal artery was totally occluded or merely stenosed, and whether the stenosis was due to atheroma or fibromuscular dysplasia. Differences between groups were evaluated by analysis of variance.
Methods In 46 patients who underwent renal angioplasty, 24-hour urine protein was measured before and at least 4 weeks after renal angioplasty, the techniques of which have been described in detail.” All patients had hypertension (average pretreatment blood pressure of at least 160/95 mm Hg], renal artery stenosis and a reduction in transluminal diameter of 1 or both renal arteries of at least 75% on renal arteriography. The therapeutic effects of angioplasty on blood pressure From the Cardiovascular Center, The New York Hospital-Cornell University Medical Center, New York, New York. This study was supported by Grants HL 18323 and RR 00047 from the National Institutes of Health, Bethesda, Maryland. Manuscript received July 9. 1986; revised manuscript received August 6, 1986, accepted August 7,1986. Address for reprints: Thomas Pickering, MD, DPhil, New York Hospital-Cornell Medical Center, 525 East 68th Street, Starr-4, New York, New York 10021.
Results Comparison of proteinuria in renovascular and essential hypertension: Patients with atheromatous renal artery stenosis were separated into 4 groups: unilateral stenosis with no occlusion, unilateral with occlusion, bilateral with no occlusion, and bilateral with occlusion of 1. renal artery. Patients with fibromuscu406
February
15, 1987
I
Clinlcal
Data
Renovascular hypertension Atheroma Unilateral no occlusion Unilateral occlusion Bilateral no occlusion Bilateral occlusion Fibromuscular Unilateral no occlusion Essential hypertension High renin Low renin
of Patients
JOURNAL
OF CARDIOLOGY
Volume
59
407
2500
lar dysplasia had unilateral stenosis with no occlusion. The levels of proteinuria in the 5 groups of patients with renovascular hypertension and the 2 groups with essential hypertension (high and low renin) are shown in Figure 1. The level of proteinuria was higher in all the renovascular groups than in either of the essential hypertension groups (p <0.0005], and in the latter there was no difference between high- and low-renin subgroups (average level 32 f 31 mg/24 hours in the former and 44 f 41 mg/24 hours in the latter). Within the renovascular subgroups, however, there were significant differences. The highest level of proteinuria was seen in the 2 groups of patients with 1 occluded artery (939 f 661 mg/24 hours): in the 3 groups with no occlusion, the proteinuria level was significantly lower (239 f 362 mg/24 hours, p <0.05). There was no significant difference in the amount of proteinuria according to whether the stenosis was unilateral (233 f 323 mg/24 hours) or bilateral (251 f 429 mg/24 hours]. In the renovascular groups without occlusion, the level of proteinuria was still higher (p <0.005] than in patients with essential hypertension. There was no correlation between proteinuria and blood pressure. Although renal function tended to be most severely impaired in the patients with bilateral atheromatous stenoses with occlusion of 1 renal artery, no close relation existed between serum creatinine or uric acid levels and the degree of proteinuria (Table I). The renovascular patients were also separated into 2 groups according to whether the proteinuria level was more than or less than 150 mg/24 hours. Although there was a tendency for serum creatinine levels to be higher in the high-protein uria group, this difference was not significant. Furthermore, 13 patients (7 with fibromuscular dysplasia and 6 with atheroma) with proteinuria ranging from 176 to 2,480 mg/24 hours had a serum creatinine level of 1.6 mg/dl or less. Changes occurring with angioplasty: In 23 patients (15 with fibromuscular dysplasia and 8 with atheroma), angioplasty resulted in a cure of the hypertension, and they had a significant decrease in the level of proteinuria (from 261 to 53 mg/24 hours, p
TABLE
THE AMERICAN
t
T
::\ 1500r .z? .;5 Kxx6 t XKI,!=J.----* ------ I)--07 =+l 2 LREH
--
ISEli
AS I-K -0CC
AS I-K +cxx
AS 2-K -0cc
6 AS 2-K +occ
7 FM I-K -0cc
FIGURE 1. Degree of proteinurla In 7 groups of patlents. Values are displayed as box plots: horizonfal line In box = median; fop and bottom of box = upper and lower quartiles; vertical dotted lines = 95% confidence limits of median; asterlsks = outliers; horizontal dotfedline = 150 mg/24 hours. AS = atherosclerotic renovascular disease; FM = flbromuscular; HREH = high-renln essential hypertension; I-K = unilateral stenosis; 2-K = bilateral stenosis; LREH = low-renin essential hypertension; +OCC and -0CC = wlth and without complete occlusion of 1 renal artery.
unsuccessful (2 with fibromuscular dysplasia and 10 with atheroma), no significant change occurred in the level of proteinuria (368 mg/24 hours before and 176 mg/24 hours after angioplasty).
Discussion Nearly 50% of our patients with renovascular hypertension had proteinuria greater than 150 mg/24 hours, whereas almost all of the patients with essential hypertension did not. In 2 previous studies, proteinuria has been reported to be a feature of renovascular hypertension,lv3 but these studies do not indicate whether it was the result of increased blood pressure or if the hypertension was renovascular rather than essential. In our series we could not attribute the proteinuria to more severe hypertension. Another factor that has been invoked is the renin-angiotensin system. It is well established that patients with renovascular hypertension usually do have high renin levels,g but in
Studled Blood Pressure (mm W
n
Age (v)
12 3 7 5
54 f 9 52 f 3 59 f a 64 f 6
183 178 197 196
19
38f
13
30 30
46f 57*
12 11
f f f f
Creatinine (mddl)
25/104 54/102 17/109 17/102
f f f f
10 16 14 4
1.8 1.6 1.7 1.9
f f f f
1.2 0.1 0.7 0.8
160 f
29/96
f
14
1.2 f
0.36
148 f 151 f
24189 20194
f f
13 12
1.06 f 1.2 f
0.2 0.3
Protein (mg124 hrs)
233 808 251 1,019
f f f f
213 i 44 f 32 f
322 698 429 641 317 41 30
408
PROTEINURIA
AND RENAL
ANGIOPLASTY
our seriespatientswith high-renin essentialhyperten- angioplastyonly produced a decreasein proteinuria sion did not have more proteinuria than patientswith when it also cured the hypertension. low renin levels. One factorthat did appearto be related to the degreeof proteinuria was the presenceof a References complete occlusionof a renal artery. This finding is in 1. Simon N, Franklin SS. Bleifer KH, Maxwell MH. Clinical characteristics of hypertension. JAMA 1972;220:1209-1218 fact consistentwith earlier reportsof massiveprotein- renovosculor 2. Berlyne GM, Tarill AS, Baker SBC. Renal artery stenosis and the nephrotic uria occurring in patients with renal artery stenosis, syndrome. Q J Med 1964;33:325-335. most of whom had complete occlusion of 1 renal ar- 3. Margolin EG. Merrill JP, Harrison JH. Diagnosis of hypertension due to tery,CilOas well ashigh circulating renin levels. This occlusions of the renal arterv. N Enel 1 Med 1957:256:581-588. A; Shapiro AP. Proteinuri: and nephrotic syndrome induced by finding of proteinuria in associationwith renal artery 4.reninKumarin patients with renal artery stenosis. Arch Intern Med 1980;140:1631occlusion is of potential clinical value, becauseit im- 1634. Montoliu J, Botey A, Torras A, Darnell A, Revert L. Renin-induced massive plies that if urine protein levels were monitored in 5.proteinurio in man. Ciin Nephrof 1979;11:267-271. patientswith renovascularhypertension(e.g.,after an- 6. SOS TA. Pickering TG, Sniderman K, Saddenkini S, Case DB, Silane MF. ED, Laragh JH. Percutaneous transluminal renal angioplusty in regioplasty],a sudden increaseof urinary protein could Vaughan novasculor hypertension due to atheroma or fibromusculor dysplasis. N Engl be a sign of an occluded artery. f Med 1983;307:274-279. Our finding of a decreasein urinary protein after 7. Maxwell MJ, Bleifer KH, Franklin SS. Varady PD. Cooperative study of renovoscular hypertension: demographic analysis of the study. JAMA 1972; angioplasty is consistentwith findings in earlier re- 220:1195-1204. portsshowing a decreaseafter surgery.4-5 However, in 8. Sealey JE, Laragh JH. How to do a pfosma renin assay. Cardiovosc Med previously reportedcasesthe surgerywas usually ne- 1977;2:1079-1092. 9. Pickering TG. SOS TA. Vaughan ED, Case DB, Sealey JE, Harshfield GA, phrectomy; thus, it was not clear whether improve- Laragh JH. Predictive value and changes of renin secretion in hypertensive ment of function of the diseasedkidney could be asso- patients undergoing successful renal angioplasty. Am J Med 1984;76:398-494. Takeda R, Morimoto S, Uchida K, kinoshi T, Sumitain T, Matsubara F. ciated with a decreased proteinuria. Our results 10. Effects of captopril on both hypertension and proteinuria. Arch Intern Med confirm that this was the case,becausein our patients 1980;140:1531-1533.
with serum creatinlne level, and in 26% ot the patients wlth renovascular hypertension, proteinuria was present despite a normal creatinine level. Renal angtoplasty produced a signlticant dlminution in proteinurla when it resulted In a cure of the hypertension, but no diminution was achieved it blood pressure did not decrease. (Am J Cardlol 1987;59:406-408)
In 46 patients with renovascular hypertension who underwent renal angioplasty, proteinuria (more than 150 mg/24 hours) was more pronounced than in patients with essential hypertension. The hl9hest levels were seen in patients in whom 1 renal artery was totally occluded. There was no dltterence between patients with unilateral vs bilateral renal artery stenosis. Proteinuria could not be correlated
R
enovascular hypertension is the most common form of curable systemic hypertension, but it is often undiagnosed because of the lack of a suitable screening test. Several studies show that proteinuria may be a characteristic finding in renovascular hypertension,l-3 and that it may diminish after successful surgery.4s5 Excessive renin levels have been suggested as the underlying cause. 4r5 The present study explores further the relation between renovascular hypertension and proteinuria, and determines whether renal angioplasty diminishes proteinuria.
were classified as cured, improved or failed using criteria described previously.6 The criteria were similar to those of the U.S. Cooperative Study of Renovascular Hypertension.7 The degree of proteinuria in these patients was compared with that in patients with essential hypertension, who were classified into 3 renin subgroups (high, normal and low] according to a reninsodium nomogram.8 For this study, only patients in the high- and low-renin subgroups were included. Most of the patients with renovascular hypertension were taking antihypertensive medications, whereas all the patients with essential hypertension had stopped taking medications for at least 2 weeks. Patients who at any time had been treated with captopril were excluded from the study. Patients with renovascular hypertension were separated into 5 groups according to whether there were stenoses of 1 or both renal arteries, whether 1 renal artery was totally occluded or merely stenosed, and whether the stenosis was due to atheroma or fibromuscular dysplasia. Differences between groups were evaluated by analysis of variance.
Methods In 46 patients who underwent renal angioplasty, 24-hour urine protein was measured before and at least 4 weeks after renal angioplasty, the techniques of which have been described in detail.” All patients had hypertension (average pretreatment blood pressure of at least 160/95 mm Hg], renal artery stenosis and a reduction in transluminal diameter of 1 or both renal arteries of at least 75% on renal arteriography. The therapeutic effects of angioplasty on blood pressure From the Cardiovascular Center, The New York Hospital-Cornell University Medical Center, New York, New York. This study was supported by Grants HL 18323 and RR 00047 from the National Institutes of Health, Bethesda, Maryland. Manuscript received July 9. 1986; revised manuscript received August 6, 1986, accepted August 7,1986. Address for reprints: Thomas Pickering, MD, DPhil, New York Hospital-Cornell Medical Center, 525 East 68th Street, Starr-4, New York, New York 10021.
Results Comparison of proteinuria in renovascular and essential hypertension: Patients with atheromatous renal artery stenosis were separated into 4 groups: unilateral stenosis with no occlusion, unilateral with occlusion, bilateral with no occlusion, and bilateral with occlusion of 1. renal artery. Patients with fibromuscu406
February
15, 1987
I
Clinlcal
Data
Renovascular hypertension Atheroma Unilateral no occlusion Unilateral occlusion Bilateral no occlusion Bilateral occlusion Fibromuscular Unilateral no occlusion Essential hypertension High renin Low renin
of Patients
JOURNAL
OF CARDIOLOGY
Volume
59
407
2500
lar dysplasia had unilateral stenosis with no occlusion. The levels of proteinuria in the 5 groups of patients with renovascular hypertension and the 2 groups with essential hypertension (high and low renin) are shown in Figure 1. The level of proteinuria was higher in all the renovascular groups than in either of the essential hypertension groups (p <0.0005], and in the latter there was no difference between high- and low-renin subgroups (average level 32 f 31 mg/24 hours in the former and 44 f 41 mg/24 hours in the latter). Within the renovascular subgroups, however, there were significant differences. The highest level of proteinuria was seen in the 2 groups of patients with 1 occluded artery (939 f 661 mg/24 hours): in the 3 groups with no occlusion, the proteinuria level was significantly lower (239 f 362 mg/24 hours, p <0.05). There was no significant difference in the amount of proteinuria according to whether the stenosis was unilateral (233 f 323 mg/24 hours) or bilateral (251 f 429 mg/24 hours]. In the renovascular groups without occlusion, the level of proteinuria was still higher (p <0.005] than in patients with essential hypertension. There was no correlation between proteinuria and blood pressure. Although renal function tended to be most severely impaired in the patients with bilateral atheromatous stenoses with occlusion of 1 renal artery, no close relation existed between serum creatinine or uric acid levels and the degree of proteinuria (Table I). The renovascular patients were also separated into 2 groups according to whether the proteinuria level was more than or less than 150 mg/24 hours. Although there was a tendency for serum creatinine levels to be higher in the high-protein uria group, this difference was not significant. Furthermore, 13 patients (7 with fibromuscular dysplasia and 6 with atheroma) with proteinuria ranging from 176 to 2,480 mg/24 hours had a serum creatinine level of 1.6 mg/dl or less. Changes occurring with angioplasty: In 23 patients (15 with fibromuscular dysplasia and 8 with atheroma), angioplasty resulted in a cure of the hypertension, and they had a significant decrease in the level of proteinuria (from 261 to 53 mg/24 hours, p
TABLE
THE AMERICAN
t
T
::\ 1500r .z? .;5 Kxx6 t XKI,!=J.----* ------ I)--07 =+l 2 LREH
--
ISEli
AS I-K -0CC
AS I-K +cxx
AS 2-K -0cc
6 AS 2-K +occ
7 FM I-K -0cc
FIGURE 1. Degree of proteinurla In 7 groups of patlents. Values are displayed as box plots: horizonfal line In box = median; fop and bottom of box = upper and lower quartiles; vertical dotted lines = 95% confidence limits of median; asterlsks = outliers; horizontal dotfedline = 150 mg/24 hours. AS = atherosclerotic renovascular disease; FM = flbromuscular; HREH = high-renln essential hypertension; I-K = unilateral stenosis; 2-K = bilateral stenosis; LREH = low-renin essential hypertension; +OCC and -0CC = wlth and without complete occlusion of 1 renal artery.
unsuccessful (2 with fibromuscular dysplasia and 10 with atheroma), no significant change occurred in the level of proteinuria (368 mg/24 hours before and 176 mg/24 hours after angioplasty).
Discussion Nearly 50% of our patients with renovascular hypertension had proteinuria greater than 150 mg/24 hours, whereas almost all of the patients with essential hypertension did not. In 2 previous studies, proteinuria has been reported to be a feature of renovascular hypertension,lv3 but these studies do not indicate whether it was the result of increased blood pressure or if the hypertension was renovascular rather than essential. In our series we could not attribute the proteinuria to more severe hypertension. Another factor that has been invoked is the renin-angiotensin system. It is well established that patients with renovascular hypertension usually do have high renin levels,g but in
Studled Blood Pressure (mm W
n
Age (v)
12 3 7 5
54 f 9 52 f 3 59 f a 64 f 6
183 178 197 196
19
38f
13
30 30
46f 57*
12 11
f f f f
Creatinine (mddl)
25/104 54/102 17/109 17/102
f f f f
10 16 14 4
1.8 1.6 1.7 1.9
f f f f
1.2 0.1 0.7 0.8
160 f
29/96
f
14
1.2 f
0.36
148 f 151 f
24189 20194
f f
13 12
1.06 f 1.2 f
0.2 0.3
Protein (mg124 hrs)
233 808 251 1,019
f f f f
213 i 44 f 32 f
322 698 429 641 317 41 30
408
PROTEINURIA
AND RENAL
ANGIOPLASTY
our seriespatientswith high-renin essentialhyperten- angioplastyonly produced a decreasein proteinuria sion did not have more proteinuria than patientswith when it also cured the hypertension. low renin levels. One factorthat did appearto be related to the degreeof proteinuria was the presenceof a References complete occlusionof a renal artery. This finding is in 1. Simon N, Franklin SS. Bleifer KH, Maxwell MH. Clinical characteristics of hypertension. JAMA 1972;220:1209-1218 fact consistentwith earlier reportsof massiveprotein- renovosculor 2. Berlyne GM, Tarill AS, Baker SBC. Renal artery stenosis and the nephrotic uria occurring in patients with renal artery stenosis, syndrome. Q J Med 1964;33:325-335. most of whom had complete occlusion of 1 renal ar- 3. Margolin EG. Merrill JP, Harrison JH. Diagnosis of hypertension due to tery,CilOas well ashigh circulating renin levels. This occlusions of the renal arterv. N Enel 1 Med 1957:256:581-588. A; Shapiro AP. Proteinuri: and nephrotic syndrome induced by finding of proteinuria in associationwith renal artery 4.reninKumarin patients with renal artery stenosis. Arch Intern Med 1980;140:1631occlusion is of potential clinical value, becauseit im- 1634. Montoliu J, Botey A, Torras A, Darnell A, Revert L. Renin-induced massive plies that if urine protein levels were monitored in 5.proteinurio in man. Ciin Nephrof 1979;11:267-271. patientswith renovascularhypertension(e.g.,after an- 6. SOS TA. Pickering TG, Sniderman K, Saddenkini S, Case DB, Silane MF. ED, Laragh JH. Percutaneous transluminal renal angioplusty in regioplasty],a sudden increaseof urinary protein could Vaughan novasculor hypertension due to atheroma or fibromusculor dysplasis. N Engl be a sign of an occluded artery. f Med 1983;307:274-279. Our finding of a decreasein urinary protein after 7. Maxwell MJ, Bleifer KH, Franklin SS. Varady PD. Cooperative study of renovoscular hypertension: demographic analysis of the study. JAMA 1972; angioplasty is consistentwith findings in earlier re- 220:1195-1204. portsshowing a decreaseafter surgery.4-5 However, in 8. Sealey JE, Laragh JH. How to do a pfosma renin assay. Cardiovosc Med previously reportedcasesthe surgerywas usually ne- 1977;2:1079-1092. 9. Pickering TG. SOS TA. Vaughan ED, Case DB, Sealey JE, Harshfield GA, phrectomy; thus, it was not clear whether improve- Laragh JH. Predictive value and changes of renin secretion in hypertensive ment of function of the diseasedkidney could be asso- patients undergoing successful renal angioplasty. Am J Med 1984;76:398-494. Takeda R, Morimoto S, Uchida K, kinoshi T, Sumitain T, Matsubara F. ciated with a decreased proteinuria. Our results 10. Effects of captopril on both hypertension and proteinuria. Arch Intern Med confirm that this was the case,becausein our patients 1980;140:1531-1533.