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*
Hypertension Department, Assistance Publique des
Hôpitaux de Paris/INSERM, France.
Clinical Investigation Center (CIC 9201), Assistance Publique des
Hôpitaux de Paris/INSERM, France.
Physiology Department and INSERM U356, Assistance Publique
Hôpitaux de Paris, Paris, France.
Radiology Department, Hôpital
Européen Georges Pompidou, Assistance Publique
Hôpitaux de Paris, Paris, France.
Correspondence to Dr. Michel Azizi, Clinical Investigation Center, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France. Phone: 33-1-56-09-29-12; Fax: 33-1-56-09-29-29; E-mail: michel.azizi{at}egp.ap-hop-paris.fr
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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60%) and normal renal function were included in the
study. Renal and angiographic follow-up evaluations were performed 6 mo after
PTRA. PTRA alone or combined with stenting (n = 2) was technically
successful in all patients. Repeat PTRA was necessary in two patients,
evaluated 6 mo after the second PTRA. Six mo after PTRA, total GFR had
increased slightly but significantly in the 29 patients with positive
lateralization indices. SRF and single-kidney GFR of the stenotic kidney
increased significantly, whereas concurrently the GFR and SRF of the
nonstenotic kidney decreased significantly. Six mo after successful PTRA
reducing renal ischemia, a reversal of both the hypoperfusion of the stenotic
side and the hyperperfusion of the nonstenotic side was observed, which was
accompanied by a slight increase in total GFR. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Therefore, this study aimed to evaluate prospectively the effect of PTRA on split renal function (SRF) and GFR in a well-defined population of patients with unilateral RAS, by measuring single-kidney GFR with synchronous inulin or 51Crethylenediaminetetraacetic acid (51Cr-EDTA) clearance and 99mTc-diethylenetriamine pentaacetic acid (99mTc-DTPA) scintigraphy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All antihypertensive treatments that might interfere with renal function
evaluation, such as diuretics, angiotensin converting enzyme (ACE) inhibitors,
and nonsteroidal anti-inflammatory drugs, were withdrawn at least 2 wk before
PTRA and were not reintroduced during follow-up. Patients were treated with
calcium channel blockers (n = 28), centrally acting antihypertensive
agents (n = 15), ß-blockers (n = 7), 
-blockers
(n = 3), or various combinations of these drugs. All patients were
advised to follow their usual sodium diet throughout the study.
PTRA Procedure
All PTRA were performed by the same physician (A.R.), as described
previously (5). After
angioplasty, the balloon catheter was withdrawn with the guidewire left across
the lesion until a repeat aortogram was performed to confirm satisfactory
angioplasty. When obstructive parietal damage or a recoil phenomenon was
observed, repeated, slow, long-lasting (3 to 4 min) pressure inflations were
performed, and, if necessary, a Wallstent endoprosthesis was inserted. At the
end of the procedure, renal angiography was repeated and the technical outcome
was assessed from this immediate postprocedural angiography. No antiplatelet
aggregation therapy was specifically prescribed to patients after PTRA.
Renal Vein Renin Ratio Determination
Renal vein renin release was stimulated by a single oral dose of 1 mg/kg
captopril administered 1 h before renal vein sampling. Plasma active renin
were measured by immunoradiometric assay, using a commercially available kit
(ERIA, Diagnostics Pasteur, Marnes-la-Coquette, France). A
captopril-stimulated renal vein renin ratio 1.5 was considered to be a
positive lateralization index.
GFR Determination
Creatinine clearance was estimated from plasma creatinine concentration
with the use of the Cockcroft-Gault formula
(6) and was standardized to a
body surface area of 1.73 m2. Pre-PTRA and follow-up total GFR were
determined for each patient with the use of the same technique: inulin renal
clearance (n = 17)
(7), 51Cr-EDTA renal
clearance (n = 10)
(8), or plasma
51Cr-EDTA (n = 5)
(9). Tests were carried out
after patients fasted overnight, and patients remained supine during the
clearance periods, resuming the standing position only to void.
Renal Scintigraphy and SRF Determinations
Renal scintigraphy was performed in the supine position, with the back of
the patient against a wide-field view 
camera (Helix-SPX, Elscint
Corp., Haifa, Israel) that was equipped with a low-energy, high-resolution
all-purpose collimator, which allowed visualization of the kidneys and the
heart. The 10% window was centered on the 99mTc 140 keV photopeak.
GFR measurements and pre- and postcaptopril renal scintigraphies were
performed on the same day. For precaptopril renal scintigraphy, 200 to 300 MBq
of 99mTc-DTPA was injected 30 min after oral hydration (7 ml/kg) at
8:00 a.m., i.e., during the equilibration or distribution period for
clearance determinations. At 12:00 p.m., after the completion of GFR
measurements, a single oral dose of 50 mg of captopril was given to the
patient, and postcaptopril scintigraphy was performed 1 h later at 1:00 p.m.
with the use of a single intravenous dose of 300 to 400 MBq
99mTc-DTPA. Each study included a flow study of 60 frames (64
x 64 pixels) of 1 s each and was followed by a sequence of 120 frames of
10 s each for 20 min.
SRF (%) were determined by the Patlak-Rutland method (10), with both extravascular and intravascular background corrections, with the use of subrenal and cardiac background regions of interest (ROI), respectively. The ROI of both kidneys were determined with the use of a threshold method on a summed frame (from 1 min 30 s to 2 min 30 s). The same kidney and background ROI were used for both pre-and postcaptopril studies. The same threshold values were used for follow-up studies in a given patient. Depth attenuation was corrected with the use of lateral views to determine the skin-to-kidney center distance and a linear attenuation coefficient of 0.12 cm-1 for 99mTc in soft tissues.
The split GFR of each kidney was calculated by multiplying total GFR by the SRF of the kidney concerned. We also estimated the renal blood flow (RBF) of each kidney using first-pass time activity curves generated from kidneys, heart, and right lung ROI. The values are expressed as percentages of cardiac output (RBF/CO, %), as described by Peters (11).
The criteria for a positive captopril renal scintigraphy were a decrease in
SRF of at least 10% or a decrease in SRF of 5 to 9% accompanied by a
time-to-peak delay 120 s with a concomitant increase in residual activity
20% in the postcaptopril scintigraphy when compared with the precaptopril
values
(12,13).
Pre-PTRA and follow-up GFR measurement and SRF studies with the use of 99mTc-DTPA renal scintigraphy were, in each case, planned for the week preceding the angiographic procedures. They were performed between 8:00 a.m. and 12:00 p.m., after patients had fasted for 12 h, to reduce GFR fluctuations caused by protein intake and the circadian rhythm in GFR.
Follow-up Evaluations
Follow-up studies, which involved BP, biologic, GFR, scintigraphic, and
arteriographic evaluations for all patients, were performed within 6 mo of
PTRA, with a minimum observation period of 3 mo. When significant angiographic
restenosis (60%) that required repeat PTRA was observed, follow-up
evaluation was planned for 3 to 6 mo later and was preceded by a control
angiography to check the effectiveness of the revascularization. In addition,
proteinuria was measured on a 24-h urine sample before and after PTRA.
The BP results of PTRA were evaluated with the use of the criteria established by the US Cooperative Study for Renovascular Surgery and modified as described by Geyskes (14). BP measurements were performed with the use of a standard sphygmomanometer, and phase V of the Korotkoff sounds was taken as diastolic BP (DBP). Patients were classified as "cured" when DBP was <90 mmHg without treatment. Improvement was defined either as a DBP >91 and <109 mmHg with a DBP decrease greater than 15% or as a DBP decrease of at least 10% plus one antihypertensive drug stopped. Treatment was considered to have failed to lower BP in all other cases.
Statistical Analyses
We carried out an ANOVA with one repeated factor (pre-PTRA and post-PTRA)
and one grouping factor (RAS cause). The assumptions of the ANOVA (homogeneity
of variance and normality) were checked for each variable, and natural
logarithmic transformations were applied as appropriate. To evaluate the
effect of PTRA on each variable, we calculated 95% confidence intervals (CI)
for the differences between the initial and final evaluations. When the limit
of the 95% CI did not cross 0, the difference between pre- and post-PTRA
values was significant.
The initial clinical characteristics of the patients with atherosclerotic
or fibromuscular dysplasia RAS were compared with the use of unpaired
t tests. The regression coefficient was estimated by the
least-squares method. Proportions were compared by the 
2
method. The STATVIEW 4.01 and SUPERANOVA programs were used for statistical
analysis (Apple Macintosh Abacus Concepts Inc., Berkeley, CA). Data are
expressed as means ± 1 SD in the tables unless otherwise specified.
Probability values below 0.05 were considered to be significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Baseline Evaluation before PTRA
Initial Characteristics. Eighteen of the 32 patients in the study
had atherosclerotic unilateral RAS, and 14 had dysplastic unilateral RAS
(Table 1). All patients had
severe hypertension at their first outpatient visit (179 ± 27/107
± 15 mmHg) independent of the RAS cause. As expected, all patients with
fibrodysplastic RAS were women (14 of 14). These patients were significantly
younger and had a significantly shorter duration of hypertension, lower plasma
creatinine, and higher creatinine clearance values than those with
atherosclerotic RAS (Table 1). Mild proteinuria (0.5 ± 0.4 g/24 h) was observed in 8 of 29 patients.
The frequencies of positive results for both renal vein renin ratio and
captopril renal scintigraphy were similar between the patients with
atherosclerotic and dysplastic RAS (Table
1). Both lateralization indices were negative in three patients
with atherosclerotic RAS. Atherosclerotic RAS were ostial in 6 of 18 patients
and truncal in the remaining. All dysplastic stenoses were truncal.
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Baseline GFR and SRF. Before PTRA, total GFR was significantly lower in patients with atherosclerotic RAS than in patients with dysplastic RAS, mainly because of the nonstenotic kidney's having a significantly lower split GFR (Table 2). The GFR of the nonstenotic kidney accounted for 66 ± 15% of total GFR (atherosclerotic, 63 ± 16%; dysplastic, 71 ± 12%; not significant). At baseline, SRF (%) was lower in patients with dysplastic RAS than in patients with atherosclerotic RAS, but the difference between the two groups was not statistically significant. This indicates that the ischemic consequences of RAS were more severe in patients with dysplastic RAS than in patients with atherosclerotic RAS. Total RBF/CO (sum of RBF/CO for both the stenotic and nonstenotic kidneys) was significantly lower in patients with atherosclerotic RAS than in patients with dysplastic RAS, because the RBF/CO of the nonstenotic kidney was significantly lower in patients with atherosclerotic RAS (Table 3).
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Immediate and Long-Term Angiographic Results after PTRA
PTRA alone or combined with stenting of the RAS was technically successful
in all patients. Immediate post-PTRA angiography showed either no residual
stenosis or a residual stenosis of <30%. In two patients with
atherosclerotic RAS, we observed a recoil phenomenon that led to the insertion
of a Wallstent endoprosthesis. The immediate postprocedural angiography showed
no residual stenosis for these two patients.
At the first angiographic control, two patients with atherosclerotic RAS
displayed signs of severe restenosis (>75%), which required repeat PTRA.
Three to 6 mo after the repeat PTRA, control angiograms showed no significant
restenosis. Only eight of the remaining patients (six patients with
atherosclerotic RAS and two patients with dysplastic RAS) had moderate
restenosis (
50%) that did not require repeat PTRA. The median follow-up
was 6 mo (range, 3 to 12 mo) after PTRA.
Long-Term Evaluation after PTRA
BP Outcome. PTRA had a major effect on both clinic systolic BP (SBP)
and DBP in all patients. SBP and DBP decreased from their pre-PTRA levels by
33 mmHg (95% CI, 22 to 44 mmHg; P < 0.001) and 17 mmHg (95% CI, 11
to 23 mmHg; P < 0.001), respectively. The decrease in BP after
PTRA was significantly larger in patients with dysplastic RAS than in patients
with atherosclerotic RAS (SBP, 47 mmHg [95% CI, 33 to 60 mmHg) versus
22 mmHg (95% CI, 6 to 36 mmHg] [P < 0.05], respectively; DBP, 26
mmHg [95% CI, 18 to 44 mmHg] versus 11 mmHg [95% CI, 3 to 19 mmHg]
[P < 0.001], respectively). According to US Cooperative Study
criteria, 11 of 18 patients (56%) with atherosclerotic RAS and 12 of 14
patients (86%) with dysplastic RAS had their hypertension cured or improved
after PTRA (2 = 4.97, df = 2, P = 0.08). The fall in
BP was obtained with significantly fewer antihypertensive treatments than
immediately before PTRA (before, n = 2 [range, 0 to 3]; after,
n = 1 [range, 0 to 3]; P < 0.05).
Renal Function Outcome. In contrast to its effect on BP, PTRA had no effect on plasma creatinine concentration or creatinine clearance (data not shown). However, the mild proteinuria present at baseline in patients with atherosclerotic RAS decreased significantly from 0.6 ± 0.7 g/24 h to 0.2 ± 0.3 g/24 h (P < 0.05) and disappeared in all four patients who had dysplastic RAS and who had proteinuria at baseline.
GFR, SRF, and SRF Outcome. Six mo after PTRA, total GFR increased slightly but not significantly in both patients with atherosclerotic and with dysplastic RAS (mean change [95% CI], 3 [-5, 11] versus 6 [-6,16] ml/min per 1.73 m2, respectively; not significant). If we excluded the three patients for whom both scintigraphic and renal vein renin lateralization indices were negative from the analysis, the change in total GFR was statistically significant (F1, 27, P = 0.04).
In contrast, we observed major changes in the functions of each of the kidneys assessed separately: SRF and GFR of the stenotic kidney increased significantly after PTRA, regardless of RAS cause, whereas the GFR of the nonstenotic kidney decreased significantly from pre-PTRA values (Table 2). Changes in GFR were correlated significantly and positively with changes in the SRF of the stenotic kidney (r = 0.48, n = 32, P = 0.02). Total RBF/CO did not change significantly after PTRA, although a significant increase in RBF/CO of the stenotic kidney was observed (Table 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In patients with unilateral RAS, renal failure may result from both ischemia of the stenotic kidney, resulting in progressive renal fibrosis and atrophy (16), and contralateral nephroangiosclerosis or focal segmental glomerulosclerosis caused by a high filtration rate and uncontrolled BP (17). Although renal revascularization should slow this process, it is unclear whether PTRA is likely to improve renal function and ultimately to prevent end-stage renal failure in patients with renovascular disease. Most studies (randomized or otherwise) that evaluated renal outcome after PTRA with or without stenting (2,3,4,18), especially in patients with unilateral RAS, reported no benefit in terms of renal function. The progressive nature of the consequences of ischemia in both kidneys, especially in patients with atherosclerotic disease, results in irreversible damage to the renal parenchyma. However, the lack of detection of a significant renal effect of PTRA also results from methodologic problems. The use of markers of total GFR, such as plasma creatinine concentration and creatinine clearance, and of markers that do not evaluate separate kidney function and the absence of a standardized evaluation procedure reduce the probability of detecting a significant change in renal function.
The main objective of this study was to evaluate prospectively, in standardized conditions, SRF outcome after PTRA in a welldefined population of patients with unilateral RAS, with the use of sensitive markers of total and separate renal function. Patients with renal failure (creatinine clearance <60 ml/min per 1.73 m2) were excluded, to increase the probability of detecting significant changes in SRF after renal revascularization. Renal insufficiency in patients with unilateral RAS is indicative of damage to both the stenotic and the nonstenotic kidney, and this damage is less likely to be reversed by revascularization (19). To increase the probability of detecting significant changes, we evaluated post-PTRA BP and renal function outcomes after demonstrating the successful revascularization of the stenotic kidney by performing a control renal angiogram in all patients. Significant restenosis that required repeat PTRA was detected in two patients. At the final evaluation, none of the patients had more than 50% restenosis, and mild restenosis (30 to 50%) was observed in only four patients.
With the use of sensitive indices of global and separate renal function, our results show that PTRA, besides its beneficial effects on BP, consistent with previous reports (1,2,3,4), had detectable beneficial effects on total renal function and SRF 3 to 6 mo after successful revascularization. Renal revascularization induced a significant increase in the split GFR of the stenotic kidney and a significant decrease in the split GFR of the nonstenotic kidney, accompanied by a nonsignificant increase in total GFR. The lack of a significant increase in total GFR may be due to (1) the small size of our sample of patients, which reduced the power to detect a significant increase in GFR after PTRA; (2) the normality of baseline GFR measurements; and (3) the inclusion of patients with negative lateralization indices, which increased variability in the response to angioplasty. Indeed, if the three patients with negative lateralization indices were excluded from the analysis, total GFR increased significantly after PTRA.
The small size of the increase in total GFR after angioplasty was due mainly to the increase in GFR of the stenotic kidney and is consistent with previous studies (4,20) but not all (21). In fact, a significant correlation was observed between changes in GFR after PTRA and changes in SRF of the stenotic side. The increase in renal function on the stenotic side probably was due to the increase in RBF, as shown by the significant increase in the fraction of the cardiac output delivered to the stenotic kidney after PTRA.
Effects of PTRA on the Nonstenotic Side
This study provides new information concerning changes in the GFR and SRF
of the contralateral, nonstenotic kidney after PTRA of the stenotic RAS.
Before PTRA, total GFR was maintained at a normal level, despite hypoperfusion
in the stenotic kidney because of a compensating hyperfiltration in the
contralateral, nonstenotic kidney. Using split intrarenal hemodynamics in the
stenotic and contralateral kidneys of patients with unilateral RAS, Kimura
et al. (22) showed
that both GFR and hydrostatic pressure were significantly higher in the
contralateral kidney than in the stenotic kidney. Their results indicate that
in the contralateral kidney, afferent arteriolar vasoconstriction does not
occur as to compensate for the impaired renal function in the stenotic kidney
and to keep renal function normal. This results in the transmission of high
systemic BP to the glomerular capillaries, resulting in glomerular
hypertension
(23,24).
Glomerular hypertension and hyperfiltration in the contralateral kidney may
result in further long-term renal damage, as observed in experimental rat
models (25).
Renal revascularization by PTRA reversed both the hyperfiltration of the nonstenotic kidney and the hypoperfusion of the stenotic kidney, facilitating the establishment of a new equilibrium in the distribution of renal function between the two kidneys. The decrease in split GFR of the contralateral kidney after PTRA may also have long-term beneficial effects by reversing hyperfiltration and glomerular hypertension within that kidney. In the 2K-1C rat model, unclipping the renal artery equilibrates glomerular hemodynamics between the two kidneys by inducing a decrease in the GFR and the RBF of the nonstenotic kidney and an increase in the GFR and the RBF of the stenotic kidney, whereas the administration of an ACE inhibitor increases the difference between the two kidneys despite having similar BP-lowering effects (26). In the same experimental model, ACE inhibitors also have been shown to protect the contralateral kidney from histologic damage while aggravating ischemic lesions in the ipsilateral kidney (27).
In this study, the reversal of hyperfiltration on the nonstenotic side and hypoperfusion on the stenotic side by PTRA was accompanied by a significant decrease in proteinuria in patients with this condition, probably indicating a partial reversal of the glomerular damage. Halimi et al. (28) showed that in patients with atherosclerotic renovascular disease, albuminuria may be used as a marker of preexisting intrarenal vascular and glomerular damage. The persistence of mild proteinuria in some of our patients with atherosclerotic RAS after PTRA may be due to autonomous glomerular lesions (29).
Finally, as expected, patients with fibromuscular dysplasia displayed greater improvements in renal function than did patients with atheroma, as both age and the duration of hypertension, which are determinants of contralateral kidney damage, were significantly higher in patients with atherosclerotic RAS. The significantly lower pre-PTRA GFR values in patients with atherosclerotic RAS than in patients with fibromuscular dysplasia is consistent with this hypothesis. Patients with atherosclerotic RAS also are more likely to have histologic lesions within both kidneys as a result of mechanisms other than renovascular hypertension (19,29,30).
In conclusion, after 6 mo, successful renal revascularization to relieve renal ischemia in patients with unilateral RAS is accompanied not only by improvements in BP control but also by improvements in split and possibly global renal function. Our study was prospective and carefully designed, but individual patients served as their own controls. It is likely—yet not documented—that giving control patients medication alone would have maintained a functional imbalance between the stenotic and nonstenotic kidneys with harmful renal consequences in the long-term. Our findings suggest that the renal benefits of PTRA have been underestimated in patients with unilateral stenosis. Randomized prospective studies are required to confirm that the establishment of a new equilibrium in renal function between the two kidneys after PTRA has long-term beneficial renal effects and prevents further changes in renal function, thereby reducing the incidence of end-stage renal failure in patients with renovascular disease.
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