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*
Departments of Nephrology and Hypertension, University Medical Center,
Utrecht, The Netherlands.
Department of Radiology, University Medical Center, Utrecht, The
Netherlands.
Department of Internal Medicine, Twenteborg Hospital, Almelo, The
Netherlands.
Correspondence to Dr. Jaap J. Beutler, Department of Nephrology and Hypertension, University Medical Center, Room F03.226, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. Phone: 31-30-2507329; Fax: 31-30-2543492; E-mail: j.j.beutler{at}digd.azu.nl
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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20% in 12 mo). The median
follow-up period was 23 mo (interquartile range, 13 to 29 mo). Angioplasty to
treat restenosis was performed in 12 cases. Five patients reached end-stage
renal failure within 6 mo, and this was related to stent placement in two
cases. Two other patients died or were lost to follow-up monitoring within 6
mo, with stable renal function. For the remaining 56 patients, the treatment
had no effect on serum creatinine levels if function had previously been
stable; if function had been declining, median serum creatinine concentrations
improved in the first 1 yr [from 182 µmol/L (135 to 270 µmol/L) to 154
µmol/L (127 to 225 µmol/L); P < 0.05] and remained stable
during further follow-up monitoring. In conclusion, stent placement, followed
by patency surveillance, to treat ostial atherosclerotic renal artery stenosis
can stabilize declining renal function. For patients with stable renal
dysfunction, the usefulness is less clear. The possible advantages must be
weighed against the risk of renal failure advancement with stent
placement. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Renal failure attributable to atherosclerotic renal artery stenosis is increasingly being recognized as an important cause of renal insufficiency (6). It is even one of the leading conditions requiring renal replacement therapy among middle-aged and elderly populations (6,7). With an aging population, its prevalence can be expected to increase. Patients who require dialysis because of atherosclerotic renal failure have poor prognoses (8). Therefore, the focus of treatment has shifted to the prevention of renal failure (5,9), but the usefulness of arterial stenting is uncertain. The group at risk to develop progressive ischemic nephropathy most likely includes patients in whom this process is already underway, i.e., patients with increased serum creatinine concentrations. Stenting experience in this group is limited (4,10). Beneficial effects were reported for patients with progressive renal failure in one study, but follow-up periods were short and survival times were very short (11).
We prospectively studied the long-term effects of renal artery stent placement, followed by angiographic patency surveillance, for patients with ostial atherosclerotic renal artery stenosis and renal dysfunction. We investigated whether this policy would have a favorable effect on the course of renal function, specifically for patients exhibiting progressive renal dysfunction.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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50% reduction in the luminal diameter within the first 10 mm of the aortic
lumen. Patients were selected on the basis of the finding that stenosis
contributed to their renal dysfunction. This was established by positive
captopril renographic findings or by a 20% increase in plasma creatinine
levels with the standardized use of an angiotensin-converting enzyme (ACE)
inhibitor (12). Exclusion
criteria were a history of cholesterol embolism, contraindications for
anticoagulant medication, small size of the affected kidney (pole-to-pole
distance of <8 cm), <25% function detected by renography, or a renal
artery diameter of <4 mm. Informed consent was obtained, and the studies
was approved by the hospital committee for studies in humans.
Protocol
BP and serum creatinine levels were measured before the intervention. The
patients continued to receive their regular medications, but ACE inhibitor
administration was discontinued at least 2 wk before this assessment. Stent
placement was performed as described by Rees
(10). Heparin was administered
(5000 IU, intravenously) during this procedure, and treatment was continued
until adequate anticoagulation was achieved with the use of orally
administered warfarin. Bilateral stenoses were treated in one session. After 3
mo, warfarin was replaced by aspirin (100 mg daily). Beginning in March 1997,
warfarin was deleted from this regimen and patients received only 100 mg of
aspirin daily, starting the day before the procedure, with heparin
administration during the procedure. The procedure was considered successful
if the residual stenosis was <50% of the luminal diameter.
The patients attended the outpatient clinic at 1, 3, and 6 mo and every 6 mo thereafter, for measurement of BP and serum creatinine concentrations. For patients receiving an ACE inhibitor, administration was discontinued at least 2 wk before the 6-mo follow-up visit. At the other time points, ACE inhibitors were withheld only for patients with deterioration of renal function and serum creatinine concentrations measured without ACE inhibition were used for evaluation. Renal angiography was repeated at 6, 18, and 30 mo. When cholesterol embolism was suspected, angiography was replaced by spiral computed tomographic angiography. Angiography was also repeated if restenosis was suspected on a clinical basis, i.e., in cases with an increase in diastolic BP of at least 15 mmHg with unchanged antihypertensive medication or an increase in serum creatinine levels of at least 20% that developed spontaneously or after the start of treatment with ACE inhibitors. Restenosis, defined as a reduction in the luminal diameter of >50%, was treated by angioplasty in the stent.
Definitions
The results of angiography were assessed in consensus readings by two
experienced vascular radiologists. The diameter of the first normal segment
distal to the stenosis was used for reference. Clinical success, as assessed
during the most recent follow-up examination, was classified according to the
guidelines of the Standards of Practice Committee of the Society of
Cardiovascular and Interventional Radiology
(13). In those guidelines,
cure of hypertension is defined as a diastolic pressure of 
90 mmHg without
antihypertensive medication. Improvement is defined as a diastolic pressure
that decreases below 90 mmHg or decreases by at least 15 mmHg with unchanged
antihypertensive medication. Any other result is classified as a failure.
Improvement in renal function is defined as a decrease in the serum creatinine
concentration of at least 20%, and deterioration is defined as an increase in
the serum creatinine concentration of at least 20%. Any other result is
defined as unchanged renal function.
Kidney Function before Treatment
For assessment of kidney function changes before stent placement, serum
creatinine concentrations in the 1 yr preceding the procedure were compared.
Only values measured without the use of ACE inhibitors were considered.
Patients were considered to have declining renal function if serum creatinine
levels had increased by at least 20% in the previous 12 mo. If serum
creatinine measurements for 1 yr before the intervention were not available,
increases in serum creatinine levels of 10% in the previous 6 mo or
15% in the previous 9 mo were considered to indicate deteriorating renal
function. Patients with smaller increases or no changes in serum creatinine
levels were considered to have stable function.
Statistical Analyses
Values are presented as medians and interquartile ranges (25 to 75%).
Changes in serum creatinine concentrations before and after procedures were
analyzed by comparisons of the slopes of plots of reciprocal serum creatinine
concentrations versus time (in months). Statistical analyses were
performed by using the Wilcoxon signed-rank test and Kaplan-Meier analysis
(for survival times and renal function preservation). P < 0.05 was
considered to indicate statistical significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immediate Effects and Complications of Stent Placement
Sixty-one of the 63 patients underwent successful stenting of at least one
renal artery. In one patient with unilateral disease, the stent was placed too
distally and a second stent failed, leaving >50% stenosis. In one patient
with bilateral stenoses, an occlusion occurred during catheterization of the
first kidney addressed, which required a surgical bypass. For three patients
with bilateral ostial stenoses, stenting failed on one side. For the other 17
patients with bilateral disease, the procedure was effective on both sides.
For seven of these patients, one of the arteries could be treated by
conventional angioplasty because the stenosis was truncal rather than
ostial.
The most common complication was local bleeding at the puncture site (Table 2). One patient required a blood transfusion. Immediate thrombosis of the stent occurred once and was successfully resolved by selective intra-arterial streptokinase administration. Seven patients (11%) exhibited clinical signs of cholesterol embolism; for five of those patients (6%), plasma creatinine levels increased by at least 20% for > 1 mo after the procedure. One patient became dialysis-dependent.
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Long-Term Patency
Repeat angiography was performed for most available patients at 6 mo (54 of
56 patients, 96%), 18 mo (36 of 42 patients, 86%), and 30 mo (12 of 18
patients, 67%). The numbers of patients with newly detected restenosis
(50%) at these time points were ten (19%), seven (19%), and two (17%),
respectively. Cumulatively, restenosis occurred in 19 cases. In 11 cases, the
restenosis was successfully treated with conventional percutaneous
transluminal angioplasty or with a second stent (n = 1). For one
patient with a patent contralateral renal artery, nephrectomy was performed
because of an aneurysm that had developed behind the stent. No action was
taken in the other seven cases, because BP was well controlled and kidney
function seemed stable, without deterioration, during standardized exposure to
an ACE inhibitor.
Follow-up angiography was complicated by a temporary loss of renal function because of a cholesterol embolism in one patient. No permanent loss of renal function attributable to the angiography was observed.
Renal Function
Twenty-eight patients were classified as having stable renal dysfunction
before stenting. Nine of those patients had unilateral disease. One became
dialysis-dependent after 5 mo. One patient died at 6 mo, with end-stage renal
failure. Of the remaining patients in this group, renal function improved for
two, remained unchanged for 18, and declined for six. Serum creatinine levels
were, by definition, stable in the period before the stent procedure and did
not change in the 1 yr after the treatment
(Table 3). The change in renal
function, expressed as the change in 1/serum creatinine concentration per
month, was -2.3 (-5.3 to 1.6) x 10-5 L/µmol per mo before
stent placement and -3.3 (-6.7 to 4.9) x 10-5 L/µmol per
mo in the subsequent 1 yr (P = 0.20, Wilcoxon signed-rank test)
(Figure 1). At 12 mo, ACE
inhibitors were used by 11 patients (42%) (for evaluation of kidney function
during ACE inhibition, see above). During additional follow-up monitoring
[median, 26 (14 to 42) mo], serum creatinine levels remained unchanged
(Table 3).
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Thirty-five patients, of whom six had unilateral disease, were considered to have deteriorating renal function before stent placement. Of these, one required dialysis 3 mo after stent placement and two others died within 6 mo, with predialysis serum creatinine levels. The stent placement did not clearly alter the rate of renal function decline for these three patients. One more patient died within 6 mo, and another was lost to follow-up monitoring at 4 mo, after experiencing a cerebrovascular accident. For these two subjects, the stent placement stabilized renal function. Of the remaining 30 patients in this group, kidney function improved for six, remained unchanged for 20, and declined for four. Serum creatinine levels, which by definition were increasing in the period before stent placement, had improved after 1 yr (Table 3). The decrease in renal function, i.e., -29.0 (-41.2 to -17.1) x 10-5 L/µmol per mo in the period before stenting, was reversed into improvement, 5.3 (-0.8 to 8.4) x 10-5 L/µmol per mo (P < 0.001, Wilcoxon signed-rank test) (Figure 1). At 12 mo, ACE inhibitors were used by nine patients (30%), which was not significantly different from the percentage of patients using ACE inhibitors in the group with stable renal function [9 of 35 (30%) versus 11 of 28 (42%)]. During additional follow-up monitoring [median, 23 (19 to 29) mo], one patient became dialysis-dependent after 27 mo. For the other patients, plasma creatinine levels remained stable (Table 3).
The cumulative number of patients who developed at least 20% decreases in
renal function is presented in Figure
2. In 23 (13 to 36) mo, 15 of the 63 patients (24%) exhibited
deterioration, and six of those patients reached end-stage renal failure.
These latter patients exhibited a median baseline serum creatinine
concentration of 326 µmol/L (range, 199 to 450 µmol/L). For further
analysis of whether increased baseline serum creatinine concentrations are
associated with poor outcomes, patients were divided into two groups,
i.e., patients with mild renal failure (serum creatinine
concentration of 300 µmol/L) and patients with severe renal failure
(serum creatinine concentration of >300 µmol/L). Baseline measurements
indicated severe renal failure for ten patients, of whom five (50%) exhibited
worsening of their renal function; this result was significantly different
from the outcomes for patients with mild renal failure (10 of 53 patients
[19%]; P < 0.05). None of the 15 patients with unilateral stenosis
experienced deterioration of renal function after stent placement; renal
function improved for two patients, and no change in serum creatinine levels
was observed for the remaining patients.
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BP
Median baseline and follow-up systolic and diastolic BP values and the
number of antihypertensive medications for all patients are presented in
Table 4. Systolic and diastolic
BP had decreased significantly by 6 mo after stent placement (P <
0.001), and this gain seemed to be durable. At the latest follow-up
examination (at least 6 mo, i.e., 56 patients), improvement or cure
of hypertension was observed for 50% (28 of 56 patients) and 9% (5 of 56
patients) of patients, respectively.
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Survival Rates
Twelve patients, one of whom was undergoing dialysis, died, after a median
period of 9.5 mo (range, 4 to 42 mo). The Kaplan-Meyer survival curve is shown
in Figure 3. In eight cases,
death could be attributed to a cardiovascular cause. No procedure-related
death or death within 30 d of stent placement was noted.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A recent meta-analysis demonstrated that, of 148 patients who underwent stent placement, mainly for treatment of atherosclerotic renal artery stenosis and renal failure (serum creatinine levels of > 133 µmol/L), 74% responded with stable function or improvement of renal function (4). Data for the patients were collected from nine studies, and in most studies the follow-up period was <1 yr. We observed a similar rate (76%) of stable or improved renal function, however, with considerably longer follow-up periods. In this respect, it was probably important that monitoring and treatment of restenosis were essential parts of our policy.
To establish the clinical value of stent placement for patients with
atherosclerotic renal artery stenosis and renal failure, we separately
evaluated patients who had exhibited demonstrably declining renal function in
the previous 1 yr. The observation that renal artery stent placement could
retard progressive renal failure was recently reported by Harden et
al. (11). Their study
included 23 patients, but the follow-up period was only 8 mo. Pretreatment
renal function (mean serum creatinine concentration, 257 µmol/L) was worse
than in our study, and stent placement could not prevent 20% of their patients
from rapidly becoming dialysis-dependent. Harden et al.
(11) and others
(4) have suggested that
significantly increased serum creatinine levels are associated with poor
outcomes. That association was confirmed in this study. The six patients who
experienced progression to end-stage renal failure exhibited a median baseline
serum creatinine level of 326 µmol/L (range, 199 to 450 µmol/L), which
was well above the median for the whole group (171 µmol/L; range, 121 to
650 µmol/L). Furthermore, the percentage of patients with deterioration of
renal function after stenting was twice as high for patients with baseline
serum creatinine levels of 300 µmol/L, compared with individuals with
serum creatinine concentrations of <300 µmol/L (50 versus 19%,
P < 0.05). The 2-yr survival rate for the Scottish population
investigated (11), which was
only 40% because of widespread cardiovascular disease, was also much lower
than that for the population we studied. It is obviously difficult to study
the long-term advantages of stenting for renal function control in a
population with such a high cardiovascular risk. Our study of patients with
clearly less cardiovascular risk demonstrates that stent placement, with
subsequent arterial patency surveillance, can indeed stabilize previously
declining renal function for years. In view of the progressive nature of
ischemic renal failure (14,
15), it is likely that, at
least for some of those patients, the development of terminal renal failure
can be postponed.
The reported rate of restenosis in the first 1 yr after stent placement in cases of ostial atherosclerotic renal artery stenosis varies between 0 and 39% and currently averages 10 to 15% (4). Data for later follow-up periods are scarce. Henry et al. (16) reported primary patency rates of 92% after 1 yr and 79% after 2 yr, suggesting undiminished development of restenosis in the second year. However, only 15 patients were monitored for 2 yr, and angiography was performed only when restenosis was suspected on the basis of ultrasound findings. Blum et al. (17) observed primary patency rates of 92% after 1 yr and 84% after 2 yr; 27 patients were monitored for 2 yr. We observed a somewhat higher restenosis rate, probably because we included more patients with bilateral disease. More importantly, those studies and our data indicate undiminished restenosis rates after the first 1 yr.
In their meta-analysis, Isles et al. (4) stated that most authors agree that restenosis is common enough to justify follow-up monitoring and reintervention. However, the reported experience with this follow-up policy in studies of meaningful duration is very limited (16,17,18). In our study, restenosis could be treated successfully with angioplasty, which confirms the general experience (10). We did not compare our policy with that of neglecting restenosis and thus cannot quantify how much surveillance for and treatment of restenosis contribute to the prevention of renal function decline. However, we presume that restenosis contributes to ischemic nephropathy as much as does primary stenosis. With this approach, we achieved the same preservation of renal function as observed by others in short-term studies. Duplex ultrasonography has emerged as a safe, inexpensive, sensitive tool for the assessment of restenosis of renal artery stents in the majority of the patients (19). We therefore recommend this method, instead of repeated angiography, for the follow-up monitoring of these high-risk patients for complications associated with the invasive procedure.
Whether and for which patients stenting will be cost-effective with the present policy can be answered only in randomized studies. Some points can be made. First, the complications of stenting and reinterventions must be considered in the evaluation. The most feared complication is widespread cholesterol embolism, which sometimes causes renal failure or even death. In this study, two patients developed end-stage renal failure, probably because of the stent placement. This risk is probably worse for patients with poorer pretreatment renal function (4, 11). Second, it has been commonly noted that stenting and other methods of renal revascularization may decrease hypertension and the need for antihypertensive drugs (4, 10, 11). This effect was confirmed in this study. However, it may play no more than a secondary role, compared with renal failure prevention, in a cost-effectiveness study. Third, a favorable effect of arterial patency restoration may be much more difficult to demonstrate for patients with previously stable renal function. If, in correspondence to our data, the best result is that renal function remains stable after the procedure, whereas some patients experience accelerated renal function decline, we should obviously not subject such patients to the burden and risk of this treatment. However, the long-term natural course for these patients in relatively stable condition is uncertain, and a randomized study is required to determine whether stenting might still be useful for this group. Finally, ischemic nephropathy is a complex disease that also involves lipid abnormalities, aging, endothelial dysfunction, hypertensive nephroangiosclerosis, areas of glomerular hypertension and segmental glomerulosclerosis, and interstitial fibrosis (20, 21). The finding that stent placement can control the progression of renal failure clearly indicates the role of stenosis in this progression but obviously does not exclude the relevance of other contributing and possibly treatable factors. In this respect, it is of note that, during the study, almost 70% of the patients used statins, which were recently demonstrated to be able to ameliorate the progression of renal failure (22).
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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