Abstract
The authors evaluated the effectiveness of percutaneous renal revascularization (PRR) with stenting for the treatment of atherosclerotic renal artery stenosis (ARAS) in patients with coronary artery disease and the usefulness of captopril renal scintigraphy for predicting clinical outcomes after PRR. Sixty‐four consecutive patients, referred for evaluation of suspected ARAS, after coronary angiography, underwent baseline captopril renal scintigraphy followed by renal angiography. Forty‐four patients (68.7%) were diagnosed with a significant ARAS≥ 60% and were treated with PRR plus medical therapy. Twenty‐four months after PRR, 86.4% and 73.3% of patients showed a hypertension and renal benefit, respectively. Captopril renal scintigraphy positivity had moderate sensitivity and high specificity in predicting a hypertension and renal benefit. In patients with ARAS≥ 70%, the sensitivity and specificity were 100% for both a hypertension and renal benefit. PRR for ARAS conferred a substantial benefit in patients with a high coronary artery disease burden. Captopril renal scintigraphy was highly accurate in predicting clinical outcomes.
Keywords: captopril renal scintigraphy, percutaneous renal revascularization, renal artery stenosis, renovascular hypertension
1. INTRODUCTION
Atherosclerotic renal artery stenosis (ARAS) is a clinical entity characterized by: (1) renovascular hypertension (RVH), (2) ischemic nephropathy, and (3) cardiac decompensation syndromes, such as flash pulmonary edema, refractory heart failure, and unstable angina.1 There has been a continuing debate regarding the role and effectiveness of percutaneous renal revascularization (PRR) in the treatment of ARAS over the past 15 years. Initial studies of percutaneous transluminal angioplasty showed slightly positive outcomes favoring percutaneous transluminal angioplasty.2, 3 During this period, treatment of ARAS has evolved from simple percutaneous transluminal angioplasty to balloon‐expandable stent placement, which has been proven superior to the former.4 Three recently published randomized controlled trials5, 6, 7 showed no benefit of PRR with stent placement compared with medical therapy (MT) alone.
Given that only 9% to 16% of patients with hypertension who have ARAS can be cured after renal stenting, it is reasonable to wonder why a procedure with a technical success rate of >95% results in such a poor clinical response.8 The answer is that the anatomically successful revascularizations were performed in patients with hemodynamically nonsignificant ARAS lesions. Indeed, the visual estimation of ARAS is an inadequate method to select patients for PRR.9 Therefore, hemodynamic or physiologic assessment of ARAS could be an approach to avoid overdiagnosis or underdiagnosis of significant stenotic lesions and to improve patient selection for PRR. Several invasive and noninvasive imaging and functional tools have been adopted to assess the hemodynamic significance of ARAS. The invasive tools, which include translesional pressure gradients10 fractional flow reserve11 and intravascular ultrasound,9 can help in the selection of proper lesions that necessitate revascularization and eventually improve clinical response rates. Regarding the noninvasive assessment of the hemodynamic significance of ARAS, the literature remains contradictory on the value of B‐type natriuretic peptide12, 13 and the renal resistive index.14
Since the principal mechanism involved in ARAS is activation of renin‐angiotensin cascade, it is assumed that a test capable of unmasking renin activation can reliably predict clinical outcomes after treatment. Captopril renal scintigraphy (CRS), which is regarded as such a test, has the dual advantage of detecting renal arterial stenosis and, when positive, may also predict response to treatment. CRS has been reported to be highly sensitive (87%–96%) and highly specific (85%–95%) in detecting ARAS,15, 16, 17, 18 whereas in other studies the results were less impressive.19, 20, 21 Currently, CRS is not recommended as a screening test for the diagnosis of ARAS22, 23 in patients suspected of having RVH. Controversy also exists regarding the predictive value of CRS in identifying patients who can benefit from PRR. While in several noncontrolled studies a positive result on CRS was predictive of improvement of hypertension after PRR,16, 17, 24, 25 in other studies the CRS was not useful for patient selection before PRR.26, 27 However, CRS has not been evaluated as an early predictor of clinical outcomes after correction of ARAS in patients with severe cardiovascular disease burden such as those with established coronary artery disease (CAD) and peripheral vascular disease (PVD). The prevalence of ARAS in patients undergoing coronary angiography with suspected CAD is markedly high ranging from 11% to 38.5% in published series.28, 29
This study was undertaken to: (1) evaluate the long‐term effects of PRR in addition to MT on blood pressure (BP) and renal function, and (2) examine the role of CRS as a predictive tool of clinical outcomes after PRR in a selected group of patients with high‐risk CAD and poorly controlled hypertension.
2. METHODS
2.1. Patients
Participants were recruited from cardiology clinics, where they underwent coronary angiography for assessment of CAD. Indications for coronary angiography in these patients included further assessment of angina in its many forms, evaluation of acute coronary syndromes, positive stress tests with or without symptoms (silent ischemia), coronary artery calcification, chest pain of uncertain etiology, valvular heart disease, and arrhythmias. Between January 2009 and December 2011, 506 consecutive patients underwent abdominal aortography at the conclusion of coronary angiography. ARAS (defined as a decrease in luminal diameter of >50%) was depicted in 78 patients, who were subsequently referred to the renal clinic for further RVH evaluation and treatment. Of these 78 patients with suspected ARAS, 66 patients were eligible for study participation.
Patients were included if they had hypertensive BP values >160 mm Hg systolic or 90 mm Hg diastolic while taking two or more antihypertensive drugs, as well as one of the following predefined criteria: (1) atherosclerotic disease (CAD or PVD); (2) unexplained mild renal dysfunction, defined as a modest elevation of serum creatinine (sCr) <2 mg/dL; and (3) flash pulmonary edema. Exclusion criteria were renal artery stenosis caused by fibromuscular dysplasia, chronic kidney disease (CKD) from a known cause other than ischemic nephropathy, and kidney length <8 cm by ultrasonography. Clinical enrollment data recorded for all patients included age, sex, body mass index, renal function (sCr and estimated glomerular filtration rate [eGFR] using the modification of diet in renal disease formula), BP level, antihypertensive drugs taken during the study, and other atherosclerotic risk factors (diabetes mellitus, dyslipidemia, former and current cigarette smoking combined, and history of CAD or PVD). CAD was defined as >60% stenosis in one or more coronary arteries. PVD was defined as a medical history of intermittent claudication, transient ischemic attack or stroke, therapeutic interventions, and artery stenosis >60% on imaging studies. Patients with diabetes mellitus with proteinuria >0.3 g/d were excluded by protocol. The study was approved by the ethical scientific committee of the University Hospital of Heraklion, Greece. All study participants provided written informed consent.
2.2. Captopril renal scintigraphy
A protocol of two‐stage examination was used. First, the examination included an oral administration of captopril 50 mg taken 60 minutes before performance of renal scintigraphy with 370 to 740 MBq of 99mtechnetium‐mercapto‐acetyl‐triglycine. Patients were instructed to stop taking antihypertensive drugs inhibiting the renin‐angiotensin system for 3 to 5 days before the study. Forty‐eight hours later, a conventional renal scan was performed when abnormalities were found in the provocative study.
Criteria for predicting clinical success after revascularization (positive CRS) were: (1) improvement in split renal function of at least 5% from the affected side (conventional versus captopril scan), (2) decrease of time to peak activity of at least 300 seconds, and (3) reduction of parenchymal transit time of at least 20%. When these conditions were not satisfied, the test was considered negative and a poor clinical response was predicted.
2.3. Percutaneous renal revascularization
Within 2 weeks after CRS, digital subtraction angiography was performed in all patients irrespective of CRS results. PRR was performed via retrograde femoral or brachial approach. For digital subtraction angiography and positioning the stent, 6‐F 45‐cm long renal‐guiding sheaths were used. The percentage of stenosis was calculated from the minimal residual lumen diameter and the average diameter in the normal portion of the renal artery on digital subtraction angiography. A diameter reduction ≥ 60% was considered as significant ARAS, while a diameter reduction < 60% was considered as nonsignificant ARAS. Patients with significant ARAS ≥ 60% were treated with PRR in combination with antihypertension drug treatment, whereas patients with nonsignificant ARAS were not subjected to PRR and constituted the MT group. Patients in both study groups received antihypertension treatment aiming to BP targets < 140/90 mm Hg, if possible. The study included balloon‐expandable bare metal stents with diameters ranging from 5 to 7 mm. The procedure was considered technically successful when angiography showed complete stent‐vessel wall apposition, complete lesion covering, and <20% residual diameter stenosis.
2.4. Follow‐up
Patients were invited for follow‐up visits 3 and 24 months after the procedure, where BP measurement, sCr levels, and evaluation of antihypertensive treatment were conducted. All BP measurements were obtained after a 10‐minute period of rest. Three successive measurements separated by 2 minutes were obtained with the use of an oscillometric device, and the mean of the last two measurements was recorded for analysis. From the patient's list of medication, all antihypertensive agents were converted to a defined daily dose (DDD)30 value for each medication, and combination therapies were calculated for each agent. Finally, all DDDs were added to a single score value. We also calculated the number of antihypertensive medication classes. For assessment of renal function, two measurements of sCr were obtained a week apart, to reduce the variation inherent in a single measurement. The average value of the two sCr measurements was used for analysis.
2.5. Evaluation of hypertension and renal function
The impact of PRR on hypertension and renal function was evaluated according to the guidelines for the reporting of renal artery revascularization in clinical trials.31 Cure was considered if systolic BP (SBP) was lowered to <140 mm Hg and diastolic BP (DBP) to <90 mm Hg without the use of antihypertensive medication, and an improvement was considered when the above BP target or a reduction of DBP by >15% was reached with the same or reduced number of medications. Any results other than those described were considered indications of failure. Benefit was defined as cure or improvement.
The criteria used to evaluate the effect of PRR on renal function were the following:
(1) improvement: increase in the absolute value of eGFR after treatment by >5 mL/min per 1.73 m2, (2) stabilization: absolute value of eGFR within ±5 mL/min per 1.73 m2 of pretreatment values, (3) failure: deterioration in eGFR after treatment by >5 mL/min per 1.73 m2.
Benefit was defined as improvement or stabilization at the end of the study period.
2.6. Statistical analysis
The statistical program SPSS version 20 (IBM) was used for all statistical analyses. Normally distributed variables were expressed as mean ± standard deviation and non‐normally distributed variables were expressed as median (interquartile range). Univariate and multivariate logistic regression analyses were used to determine the best predictors of both the diagnosis of ARAS and clinical outcomes after PRR. The relationship between the baseline value of a continuous variable (BP and eGFR) and subsequent change over time was assessed with the Oldham method.32 A two‐factor (time × treatment) repeated measures analysis of variance design was used to analyze BP and eGFR changes across time. The receiver operator characteristics curves resulting from the regression models were developed, taking into account only significant variables. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the CRS for diagnosis of ARAS and as a predictive tool for identifying patients who would benefit from the PRR were also calculated. Changes were considered significant for P < .05 (two‐sided).
3. RESULTS
3.1. General characteristics
Of the 66 patients who consented to the study, 64 (38 men and 26 women) completed the 2‐year follow‐up period and were included in the analysis. Forty‐four patients (68.7%) were diagnosed with significant ARAS and underwent PRR, whereas 20 patients (31.2%) were diagnosed with nonsignificant ARAS and continued MT throughout the study period. Left ARAS was found in 20 patients (45.4%), right ARAS in 16 (36.4%) patients, and bilateral ARAS in eight (18.2%) patients, with an average lumen narrowing of 72.5 ± 5.3% on the main side and of 63.1 ± 4.6% on the secondary side. Coronary angiography analysis showed that 16 (25%) patients had no CAD, whereas 19 (29.6%), 17 (26.6%), and 12 (18.8%) patients had one‐, two‐, and three‐vessel disease, respectively. Forty of 48 (75%) patients with CAD had ARAS, whereas of the 16 patients without CAD, only four (25%) had ARAS. Technical success, defined as above, was achieved in all patients. Femoral hematoma occurred in one patient and renal artery dissection in another, which was cured by stent placement.
The baseline clinical characteristics of patients in the PRR group with ARAS ≥ 60% and the MT group with ARAS < 60% are shown in Table 1. Only the prevalence of CAD was significantly higher in the PRR group compared with the MT group (92% vs 40%, P < .001).
Table 1.
Patient characteristics
| Characteristic | All (N = 64) | PRR (n = 44) | MT (n = 20) | P value |
|---|---|---|---|---|
| Age, y | 64.7 ± 10.5 | 65.1 ± 9.8 | 66.2 ± 8.5 | NS |
| BMI, kg/m2 | 28.2 ± 4.6 | 28.2 ± 4.3 | 28.1 ± 3.6 | NS |
| Sex (male/female), % | 59.4/40.6 | 59/41 | 60/40 | NS |
| Diabetes mellitus, % | 35.9 | 40.9 | 25 | NS |
| Smokers, % | 67.2 | 66 | 70 | NS |
| CAD, % | 75 | 92 | 40 | <.001 |
| PVD, % | 25 | 27.3 | 20 | NS |
| Dyslipidemia, % | 53.1 | 54.5 | 50 | NS |
| Antihypertensive drugs, % | ||||
| RAS inhibitorsa | 90.6 | 90.9 | 90 | NS |
| Diuretics | 70.3 | 72.7 | 65 | NS |
| CCBs | 64.1 | 68,2 | 55 | NS |
| β‐Blockers | 48,4 | 52.3 | 40 | NS |
| Other | 15.6 | 18.2 | 10 | NS |
| Artery stenosis, % | 65 (57–70) | 70 (65–74) | 55 (50–57) | – |
| CKD, %b | 40.6 | 43.2 | 35 | NS |
Abbreviations: BMI, body mass index; CAD, coronary artery disease; CCBs, calcium channel blockers; MT, medical therapy; NS, not significant; PRR, percutaneous renal revascularization; PVD, peripheral vascular disease.
Renin‐angiotensin system (RAS) inhibitors: angiotensin‐converting enzyme inhibitors and angiotensin receptor antagonists.
Chroninc kidney disease (CKD): percentage of patients with estimated glomerular filtration rate <60 mL/min per 1.73 m2.
3.2. Clinical outcomes after PRR
Average BP values, eGFR, and the number of antihypertensive drugs over time are reported in Table 2. Baseline SBP was significantly higher (P <.05) in the PRR group as compared with the MT group. Changes in SBP from baseline, averaged across time, fell by 15.6 mm Hg (95% confidence interval [CI], 12.3–18.8) in the PRR group, whereas it dropped by 5.6 mm Hg (95% CI, 1.1–10.4) in the MT group (P < .001). The corresponding reduction in DBP for the PRR and MT groups were 6.2 mm Hg (95% CI, 4.2–8.4) and 0.0 mm Hg (95% CI, −3.1 to 3.1), respectively.
Table 2.
SBP and DBP, eGFR, DDD, and number of antihypertensive drug classes for the 64 patients treated with PRR with MT or MT alone, assessed at baseline and months 3 and 24
| Parameter | Baseline | 3 mo | 24 mo | |
|---|---|---|---|---|
| SBP, mm Hg | PRR | 162.0 ± 18.9b | 138.8 ± 15.9a | 140.8 ± 15.4 a |
| MT | 151.1 ± 10.9 | 142.5 ± 15.2a | 143.0 ± 15.8a | |
| DBP, mm Hg | RRR | 85.8 ± 8.9 | 75.9 ± 8.3a | 76.6 ± 7.4a, c |
| MT | 81.5 ± 7.8 | 79.4 ± 8.1 | 83.6 ± 6.7 | |
| eGFR, mL/min | PRR | 68.5 ± 22 | 70.1 ± 23.1d | 68.2 ± 22.2 |
| MT | 65.9 ± 15.9 | 62.9 ± 15.7 | 61.6 ± 15.4a | |
| Drugs, No. | PRR | 3.4 ± 1.1c | 2.2 ± 1.3a | 1.7 ± 1.5a, b |
| MT | 2.6 ± 0.9 | 2.7 ± 1.0 | 2.5 ± 1.2 | |
| Drugs DDD score | PRR | 5.7 ± 1.1.7c | 3.2 ± 1.9a | 3.2 ± 2a |
| MT | 4.3 ± 1.5 | 3.8 ± 1.7 | 3.8 ± 1.8 |
Abbreviations: DBP, diastolic blood pressure; DDD, defined daily dose; eGFR, estimated glomerular filtration rate; PRR, percutaneous renal revascularization; SBP, systolic blood pressure.
P < .05 vs baseline.
P < .01 vs baseline.
P < .001 vs baseline.
P < .05 vs medical therapy (MT).
P < .001 vs MT.
P < .05 vs MT at 3 months.
None of the baseline variables, including eGFR, sCr, SBP, DBP, PVD, CAD, diabetes mellitus, and age, significantly affected the BP results when included as covariates in the analysis (data not shown).
However, when analysis was restricted to patients who underwent PRR, baseline SBP was associated with SBP changes (r = .389, P < .001) and baseline DBP was associated with DBP changes (r = .318, P < .005) at 24 months. Thus, patients with a baseline SBP > 160 mm Hg experienced a greater decrease in SBP (16.7 mm Hg; 95% CI, 7.1–26.2 [P < .001] compared with patients with a baseline SBP ≤ 160 mm Hg.
Hypertension was treated in 14 (31.8%), improved in 24 (54.6%), and remained unchanged in six (13.6%) of the 44 patients with PRR. Overall, 38 of the 44 (86.4%) patients benefited from PRR, whereas a clinical benefit was achieved in only seven of the 20 patients (35%) treated medically for hypertension (P < .001).
eGFR did not differ between groups at baseline and remained unchanged with time in the PRR group, whereas it gradually declined in the MT group (Table 2). eGFR, averaged across time, decreased in the MT group by 2.4 mL/min per 1.73 m2 (95% CI, 0.1–4.7), whereas it increased by 0.4 mL/min per 1.73 m2 (95% CI, −1.2 to 1.9) in the PRR group. When analysis was restricted to 44 patients with revascularization, changes in eGFR at 24 months correlated significantly with baseline SBP (r = .325, P <.05) and DBP (r = .433, P < .01). eGFR increased by 5.2 ± 9.6 mL/min per 1.73 m2 in patients with a baseline DBP > 85 mm Hg, and decreased by 2.9 ± 7.5 mL/min per 1.73 m2 in those with DBP ≤ 85 mm Hg. Among patients with DBP > 85 mm Hg, baseline eGFR correlated inversely with changes in eGFR (r = −0.406, P < .05). In addition, eGFR changes correlated with SBP changes (r = −0.390, P < .01) and DBP changes (r = −.347, P < .05) at 24 months.
eGFR improved in 11 (25%), stabilized in 23 (52.3%), and deteriorated in 10 (22.7%) of the 44 patients with PRR. The renal benefit did not differ significantly between the PRR (77.3%) and MT (60%) groups.
Finally, the baseline number of drugs used and the DDD scores in the PRR group were higher than those in the MT group (P < .001). Both decreased progressively (P < .001) over the follow‐up period in the PRR group, and by the end of the study, the number of drugs, but not the DDD scores, were significantly lower (P < .05) as compared with those in the MT group (Table 2).
3.3. Clinical predictors of significant ARAS
CAD, baseline SBP, CRS positivity, and treatment with three or more antihypertensive drugs were identified as univariate predictors of a significant ARAS ≥ 60% (Table 3). Multivariate analysis indicated that CAD (odds ratio, 1.9; 95% CI, 1.1–3.7) for every one‐vessel disease increment, CRS positivity (odds ratio, 3.9; 95% CI, 1.0–15.1), and treatment with three or more antihypertensive drugs (odds ratio, 4.9; 95% CI, 1.3–18.1) were associated with an increased likelihood of significant ARAS (Table 3).
Table 3.
Univariable and multivariable analyses of predictors associated with the presence of significant atherosclerotic renal artery stenosis
| Variable | Univariable analysis | Multivariable analysis | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | P value | OR | 95% CI | P value | |
| CRS (+) vs (−) | 3.95 | 1.22–12.78 | .022 | 3.91 | 1.01–15.14 | .049 |
| CAD (↑1 vessel) | 2.44 | 1.32–4.51 | .005 | 1.92 | 1.0–3.68 | .050 |
| Drugs (≥3 vs <3 drugs) | 4.95 | 1.59–15.38 | .006 | 4.92 | 1.34–18.07 | .016 |
| SAP (1 mm Hg) | 1.05 | 1.01–1.10 | .019 | – | – | – |
Abbreviations: CAD, coronary artery disease; CI, confidence interval; CRS, captopril renal scintigraphy; OR, odds ratio; SAP, systolic blood pressure.
Receiver operator characteristics curves were constructed for each of these three significant and independent predictors of ARAS ≥ 60% and the area under each curve was calculated (Table 4). The presence of two or more significant coronary lesions showed the best performance for detecting significant ARAS, as it yielded the highest area under each curve values of 0.755, followed by that of the number of antihypertensive drugs and positivity of CRS. The best results for ARAS detection were obtained when CRS was combined with the extent of CAD and the number of antihypertensive drugs, with area under each curve values increasing to 0.862. Of note, the combined specificity was similar (75%) to that of CRS. Regarding CRS specificity, among 20 patients with no angiographic evidence of significant ARAS ≥ 60%, five patients had false‐positive CRS studies. There were also 19 false‐negative CRS studies in our 44 patients with angiographically confirmed significant ARAS ≥ 60%. Three patients had bilateral disease, while eGFR of the patients with false‐negative CRS (n = 19) was not different from those (n = 25) with a positive CRS (72 ± 22 vs 66 ± 22 mL/min per 1.73 m2).
Table 4.
Diagnostic performance of parameters for identifying significant atherosclerotic renal artery stenosis
| Parameter | AUC | 95% CI | Sensitivity | Specificity | PPV | NPV |
|---|---|---|---|---|---|---|
| CRS | 0.659 | 0.530–0.773 | 57 | 75 | 83 | 44 |
| CAD | 0.755 | 0.631–0.854 | 91 | 60 | 83 | 75 |
| Drugs | 0.680 | 0.561–0.799 | 73 | 65 | 82 | 52 |
| CRS+CAD+drugs | 0.862 | 0.753–0.935 | 87 | 75 | 88 | 72 |
Abbreviations: AUC, area under the curve; CAD coronary artery disease; CI, confidence interval; CRS, captopril renal scintigraphy.
Positive predictive value (PPV) and negative predictive value (NPV) were calculated according to the following formula: (TP/TP+FP) × 100 and (TN/FN+TN) × 100, respectively, where TP=true positive, FP=false positive, TN=true negative, and FN=false negative.
3.4. CRS as a predictor of clinical outcomes after PRR
Next, we examined the value of CRS as predictor of clinical outcomes in hypertension and renal function after the correction of ARAS. According to our logistic regression analysis, a positive CRS emerged as the only independent predictor of both hypertension and renal function benefit after PRR. The area under the receiver operator characteristics curve, sensitivity, specificity, PPV, and NPV values of the CRS test are shown in Table 5. CRS positivity, suggesting a potential favorable BP response after PRR, occurred in 92.9% (13/14) of the patients who were cured, in 48% (12/25) of the patients who improved, and in none 0% (0/5) of the patients who failed (χ2=14.8, P < .001). For patients who benefited from PRR, CRS positivity had a sensitivity, specificity, PPV, and NPV of 66%, 100%, 100%,and 32%, respectively (χ2=9.2, P < .01). The test performed better in terms of sensitivity and NPV, when analysis was restricted to patients (n = 13) with ARAS > 70% (Table 5).
Table 5.
CRS as a predictor of clinical outcomes in patients with percutaneous renal revascularization
| Outcome | AUC | Sensitivity | Specificity | PPV | NPV |
|---|---|---|---|---|---|
| Hypertension benefit | |||||
| All ARAS (n = 44) | 0.720 | 66 (25/38) | 100 (6/6) | 100 (25/25) | 32 (6/19) |
| ARAS ≤70 (n = 31) | 0.786 | 54 (15/28) | 100 (3/3) | 100 (15/15) | 19 (3/16) |
| ARAS >70 (n = 13) | 1.000 | 100 (10/10) | 100 (3/3) | 100 (10/10) | 100 (3/3) |
| Renal functional benefit | |||||
| All ARAS (n = 44) | 0.803 | 71 (24/34) | 90 (9/10) | 96 (24/25) | 47 (9/19) |
| ARAS ≤70 (n = 31) | 0.642 | 58 (14/24) | 86 (6/7) | 93 (14/15) | 38 (6/16) |
| ARAS >70 (n = 13) | 1.000 | 100 (10/10) | 100 (3/3) | 100 (10/10) | 100 (3/3) |
| Both hypertension and renal functional benefit | |||||
| All ARAS (n = 44) | 0.833 | 75 (24/32) | 92 (11/12) | 96 (24/25) | 58 (11/19) |
| ARAS ≤70 (n = 31) | 0.720 | 64 (14/22) | 89 (8/9) | 93 (14/15) | 50 (8/16) |
| ARAS >70 (n = 13) | 1.000 | 100 (10/10) | 100 (3/3) | 100 (10/10) | 100 (3/3) |
Abbreviations: ARAS, atherosclerotic renal artery stenosis; AUC, area under the curve; CRS, captopril renal scintigraphy; NPV, negative predictive value; PPV, positive predictive value.
A positive CRS, suggesting a potential favorable renal outcome after PRR, occurred in 100% (11/11) of the patients whose eGFR improved, in 56.5% (13/23) of the patients whose eGFR stabilized, and in only 10% (1/10) of the patients whose eGFR deteriorated (χ2=17.3, P < .001). For patients who benefited from PRR, a positive CRS had a sensitivity, specificity, PPV, and NPV of 71%, 91%, 96%, and 47%, respectively (χ2 = 11.6, P < .001). As shown in Table 5, CRS performed better in patients with ARAS > 70% than in patients with ARAS ≤ 70%.
Finally, we examined the performance of CRS in the prediction of a favorable composite outcome, consisting of both a hypertension and renal function benefit after PRR (Table 5). A favorable composite outcome occurred in 72.7% (32/44) of patients in the PRR group and in 10% (2/20) of patients in the MT group (P < .001). The sensitivity and specificity of CRS in predicting an overall clinical benefit after PRR were 75% and 92%, respectively, whereas the corresponding numbers of the test in patients with ARAS > 70% were both 100%.
4. DISCUSSION
Our results indicate that in patients with ARAS ≥ 60% and a high prevalence of CAD, PRR in addition to MT, as compared with MT alone, resulted in a significantly lower BP, with a significant lower requirement for antihypertensive medications, without, however, a clinically important renal benefit over a 24‐month follow‐up. Although CRS was only moderately useful for diagnosing a hemodynamically significant ARAS ≥ 60%, it emerged as an important predictor of clinical outcomes after PRR.
Although the use of PRR has been shown to improve arterial patency, there is currently no clear evidence that such intervention can treat RVH and improve or prevent further progressive decline of renal function. Regarding RVH, the majority of three retrospective and nine prospective cohort studies included in a recent meta‐analysis33 reported a decrease of BP after PRR, with the mean BP falling by approximately 10 mm Hg.34 Even larger BP reductions by an average of 20 mm Hg were also reported in uncontrolled studies.35, 36 However, these findings were not confirmed in four meta‐analyses of randomized controlled trials37, 38, 39, 40 and a recent systematic review.41 These randomized controlled trials generally had major flaws in design, patient selection,42 lesion severity, sample size, outcome measurement, and clinical applicability,43, 44 and frequently excluded patients with a high‐risk clinical profile45 (advanced kidney disease, malignant or accelerated hypertension, history of unstable heart failure, or CAD) who may have benefited from PRR.7 For example, patients were randomized in the ASTRAL (Angioplasty and Stenting for Renal Artery Lesions) trial5 when the treating physician was unsure of a benefit of PRR, and patients without systolic hypertension could be enrolled in the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) trial,7 as the entry criterion for an SBP of >155 mm Hg was withdrawn in the course of the study. Some of the eligible for enrollment patients were not recruited and may have been treated by PRR by physicians who were convinced of the clinical benefit of the procedure. Thus, in both trials, patients who were likely to benefit from PRR were not included and patients less likely to benefit (ie, without hypertension) were included. In contrast, in our prospective cohort study, all patients had a functional classification for ARAS of grade III42 with poorly controlled hypertension, despite the use of several antihypertensive medications, clear evidence of renal dysfunction, and a constellation of cardiovascular risk factors, including a CAD prevalence of 92%. For instance, our patients, compared with patients in the CORAL and ASTRAL studies, had a higher prevalence of CAD (92% vs 26–50%), were treated with a higher number of antihypertensive drugs (3.4 vs 2.1–2.8), and had an overall higher CVD risk because of a higher prevalence of smoking (67% vs 20–32%).
The ASTRAL5 and CORAL7 trials have shown that patients with stable kidney function and adequate BP control do not require intervention. On the other hand, clinical evidence for the benefit of PRR in patients with the high‐risk clinical profile45 is still lacking. The present study showed a significant beneficial effect of PRR in such a high‐risk cohort of patients. Specifically, SBP and DBP, averaged across time, fell by 15.6 mm Hg and 6.2 mm Hg, respectively. Since this fall in BP was obtained with significantly fewer antihypertensive drugs, this might further indicate an incremental BP‐lowering benefit with PRR. In addition, benefits seen in some studies may be more pronounced if appropriate subgroups were to be identified. In this regard, patients with the highest baseline SBP values had the greatest decreases in SBP.13, 46 Until methods of reliably preselecting patients are available, decisions on revascularization should be made on an individual patient basis. In this regard, we propose that patients should not randomly receive PRR based on a presence of a mere anatomic stenosis, but should be selected on the basis of: (1) clinical criteria (acute or subacute change in BP control or rate of CKD progression, presence of CAD and CVD burden, severity of hypertension) and (2) functional criteria (hemodynamic significance of ARAS), including CRS positivity, as described below.
Regarding renal function, data from observational studies suggest that revascularization may stabilize renal function in patients at high risk for progressive ischemic nephropathy, particularly those with CKD.34, 47, 48 Our results further confirm these previous findings, since time‐averaged eGFR increased slightly by 0.4 mL/min per 1.73 m2 (95% CI, −1.2 to 1.9) over the whole study period. In fact, eGFR appeared to be better in the PRR group than in the MT group at 3 months, but not at 24 months. Interestingly, eGFR was significantly greater for patients with baseline SBP > 160 mm Hg or DBP > 85 mm Hg, and, among these patients, the lower the baseline eGFR the greater the chance of achieving a favorable renal response after PRR. Type of artery stenosis (unilateral or bilateral), degree of arterial stenosis, and CAD severity were not predictors of changes in eGFR after PRR. In addition, the magnitude of SBP and DBP reductions after revascularization was associated with the magnitude of eGFR increments. These data provide strong evidence that patients with severe/uncontrolled hypertension and progressive CKD may gain the greatest renal benefit from PRR.
In nearly all series, there are patients whose sCr increases, remains stable, or decreases after PRR, but sCr differences within subgroups are masked by the group's average sCr. However, a favorable effect following PRR could be identified when outcomes were categorized according to renal response. Renal function improved or stabilized in 52% to 94% of patients after PRR, according to previous observational studies,2, 8, 34, 47 while a recent meta‐analysis33 of 13 studies reported an improvement of renal function in 58% of the patients with PRR. However, there are also counterbalancing reports of worsening renal function after successful PRR.8 In our study, a functional renal benefit was achieved in 77.3% of the patients with PRR, which did not differ from that (60%) achieved in patients with MT. These inconsistent results among studies may also stem from the differential effect of revascularization on the split GFR between treated and contralateral kidney.49
In agreement with previous results28, 29 CAD emerged as a strong independent predictor of significant ARAS. As shown in Table 4, the diagnostic accuracy of the presence of two or more significant coronary lesions for detecting ARAS was superior to that of CRS positivity and the number of baseline antihypertensive drugs.
One of the main goals of the present study was to examine the usefulness of CRS, as a prognostic test to predict BP and renal function outcomes after PRR in patients with suspected RVH. Of the 44 patients who underwent PRR, CRS was positive in 25 patients and negative in 19 patients. A positive CRS had a moderate sensitivity and a high specificity to predict a post PRR hypertension benefit (62% and 100%) and a functional renal benefit (70% and 91%). In this context, a positive CRS was a strong predictor of clinical improvement after PRR, since a hypertension benefit was achieved in all (n = 25) patients with positive CRS (100% PPV). On the other hand, a negative CRS was somewhat less accurate in predicting post PRR outcomes, since eight of 19 patients with a negative CRS benefited from PRR (composite outcome). The fact, however, that 11 of 19 patients with a negative CRS failed to show any improvement after the intervention suggests that these 11 false‐negative CRS results on angiography, were actually true negative in terms of lack of response to PRR. The finding that the performance of CRS is improved when it is compared with the patients' clinical outcome rather than the results of renal angiography confirms the usefulness of CRS to determine the physiologic sequence of a known stenosis.50
Taken together these results indicate that in patients with CAD and angiographic evidence of ARAS ≥60%, a positive CRS should prompt an interventional approach, since it almost certainly predicts favorable postprocedural outcomes. In contrast, for patients with negative CRS, clinicians must rely on clinical judgment and further workup, including newer promising methods.9, 10, 11 In cases of ARAS ≥ 70%, however, a negative CRS is highly sensitive to obviate the need for further invasive investigation or revascularization.
STUDY LIMITATIONS AND STRENGTHS
The study has several limitations. First, the sample size of the study was small and, therefore, the predictability of the CRS for clinical outcomes should be prospectively verified in larger studies. Second, the absence of a properly matched control group prevented us from assessing whether PRR in addition to MT is superior to MT alone and any relevant comparisons presented here are merely descriptive. Third, since the predictive performance of CRS was investigated in patients with increased burden of CVD, this procedure may not be applicable in the general hypertensive population. Despite these limitations, our robust data analysis enabled us to: (1) identify high‐risk subsets of patients who can derive a greater benefit from PRR, and (2) substantiate the usefulness of CRS for detecting RVH in appropriately selected patients, such as patients with CAD who have ARAS ≥ 70%.
5. CONCLUSIONS
In our patients with high‐risk CAD, a favorable composite outcome was reached in 72.7% and 10% of patients treated with PRR and MT, respectively. The identification of “high‐risk” clinical characteristics, such as an SBP > 160 mm Hg or DBP > 85 mm Hg with CKD under optimal MT, can be used to predict a benefit from PRR and further suggest that more research is needed on the utility of PRR in patients with high CVD/CAD burden. A preprocedural CRS accurately predicted postprocedural outcomes, with the test reaching a sensitivity and specificity of 100% in patients with ARAS ≥ 70%.
CONFLICT OF INTEREST
The authors report no specific funding in relation to this research and have no conflicts of interest to disclose.
Stratigis S, Stylianou K, Kyriazis PP, et al. Renal artery stenting for atherosclerotic renal artery stenosis identified in patients with coronary artery disease: does captopril renal scintigraphy predict outcomes?. J Clin Hypertens. 2018;20:373–381. 10.1111/jch.13160
Tsetis and Daphnis contributed equally to this work
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