Abstract
Patients with atherosclerotic renovascular disease (ARVD) and high-risk clinical presentations have largely been excluded from randomized controlled trials comparing renal revascularization and optimal medical therapy. Here, we explore the effect of revascularization on death, progression to end-stage kidney disease (ESKD) and cardiovascular events (CVE) in a highly selected cohort of patients with ARVD.
All patients with a radiological diagnosis of ARVD referred to our tertiary centre have been recruited into a single-centre cohort study between 1986 and 2014. Patients with ≥70% unilateral or bilateral ARVD together with one or more of the following putative high-risk presentations were designated ‘high-risk’: flash pulmonary oedema (FPE), severe hypertension, rapidly deteriorating renal function. The effect of revascularization on clinical outcomes in high-risk patients, patients with bilateral severe ARVD and those with <1 g proteinuria at baseline was compared with ‘control’ patients who had the same degree of renal artery stenosis (RAS) but did not exhibit these features.
Median follow-up was 58.4 months [interquartile range (IQR) 25.4–97.3]. Revascularization was associated with a reduced risk of progression to ESKD, CVE and all combined events in patients with rapidly deteriorating renal function [ESKD: hazard ratio (HR) 0.47 (95% confidence interval, CI, 0.25–0.85), P = 0.01; CVE: HR 0.51 (95% CI 0.29–0.91), P = 0.02; Any: HR 0.51 (95% CI 0.29–0.90), P = 0.02]. High-risk patients with bilateral ≥70% RAS and those with <1 g/day baseline proteinuria also had significantly better renal and cardiovascular outcomes post-revascularization when compared with controls.
Our results indicate that revascularization may be of benefit in patients with anatomically significant RAS who present with rapidly deteriorating renal function, especially in the presence of severe bilateral ARVD or <1 g/day proteinuria.
INTRODUCTION
Randomized controlled trials (RCT) and meta-analyses [1–4] of revascularization versus medical therapy in patients with atherosclerotic renovascular disease (ARVD) have shown that revascularization does not confer added benefit to medical therapy in unselected patients, resulting in reduced enthusiasm for revascularization [5].
These studies have been criticized for enrolling a large proportion of stable patients with low-risk features [6, 7]. While most ARVD patients have ‘incidental’ disease and remain stable on medical therapy alone, some present with ‘high-risk’ clinical phenotypes that are refractory to medical therapy. These include uncontrolled hypertension, rapid deterioration of renal function or recurrent episodes of acute heart failure [8].
There is consistent, albeit non-randomized, evidence that revascularization may be of benefit in these subgroups. Observational studies have shown that revascularization can stabilize or improve renal function, delaying the need for renal replacement therapy (RRT), in selected patients with ARVD and either rapidly deteriorating or advanced renal impairment [9–12], and case reports support revascularization in patients with recurrent acute pulmonary oedema [13, 14]. While revascularization did not improve blood pressure control in RCTs, a more recent prospective but uncontrolled study of the effects of a new renal stent has shown that patients with poorly controlled hypertension at recruitment had a greater reduction in blood pressure post-revascularization compared with those with better blood pressure control [15]. In addition, our recent observational study indicates that revascularization is associated with survival benefit in patients presenting with flash pulmonary oedema (FPE) [hazard ratio (HR) 0.4 (95% confidence interval, CI, 0.2–0.9), P = 0.01] or rapidly declining renal function and refractory hypertension in combination [HR 0.15 (95% CI 0.02–0.9), P = 0.04] [16]. We have also previously shown that severity of ARVD and proteinuria also correlate with adverse outcomes in ARVD in unselected cohorts [17, 18].
Despite the lack of RCT evidence, societal guidelines still recommend revascularization in specific clinical scenarios [19, 20]. Patient selection for renal revascularization is complex and challenging, and the lack of benefit from revascularization noted in RCTs is likely due to non-targeted patient selection [21]. We hypothesized that outcomes post-revascularization are more likely to be positive in ‘high-risk’ patients with anatomically severe stenosis and without significant proteinuria (a surrogate of potentially viable renal parenchyma [22]). This would potentially aid in characterizing the specific phenotype of patients who would gain benefit from revascularization, even within those subgroups of ARVD who already meet current criteria for revascularization [19, 20].
MATERIALS AND METHODS
Patient population and data collection
The observational Salford ARVD study was established in 1986. Approval was granted by the local ethics committee. Patients with ARVD were recruited and data updated annually from hospital records. Data include age, gender, co-morbidities [diabetes, macrovascular disease (MVD), congestive heart failure (CHF)], FPE, prescribed medications, blood pressure, creatinine (μmol/L), proteinuria (g/24 h) and clinical outcomes. The degree of renal artery stenosis (RAS) was obtained from cross-sectional angiography (intravenous digital subtraction angiography, intra-arterial digital subtraction angiography, computed tomographic or magnetic resonance angiography), and recorded using a renal artery ‘patency score’; a score of 200 was equivalent to 0% bilateral stenosis, whereas a score of 0 meant 100% bilateral occlusion. Estimated glomerular filtration rate (eGFR) was calculated using CKD-EPI [23].
The date of diagnostic imaging was considered as time zero. New patients were entered into the database up until 31 August 2014 and data censoring was performed at the earliest of 11 May 2015, death or last patient encounter.
Study population
Our definition of ‘high-risk’ was based on expert consensus statements [20, 21], and patients were identified by retrospective review of the database. The definition was ≥70% unilateral or bilateral angiographic RAS with at least one of:
FPE or acute decompensated heart failure in the absence of a documented precipitating cardiac event or known reduced ejection fraction (<40%) or documented CHF.
Stage 2 hypertension (systolic ≥160 mmHg and/or diastolic ≥100 mmHg) despite three or more anti-hypertensives of which one is a diuretic [24].
Rapidly deteriorating renal function following diagnosis of ARVD, defined as an eGFR slope less than −3.0 mL/min/1.73 m2/year, this being the 25th percentile of the eGFR slope of all ARVD patients on the database [median eGFR slope −0.9 mL/min/1.73 m2/year (interquartile range, IQR, −3.0 to + 0.9)].
Patients with bilateral renal artery occlusion or unilateral occlusion and contralateral RAS <70% were excluded, as these patients are considered less likely to be candidates for revascularization. Patients who met the same inclusion criteria for RAS severity but did not have any of these three clinical presentations were designated ‘control’. Diabetic patients with retinopathy and ≥1 g/day proteinuria were excluded from both groups as they were considered to have underlying diabetic nephropathy.
Patient management
Patients were managed in accordance with contemporary vascular protective advice and UK Renal Association blood pressure targets [25, 26]. Renal revascularization was performed in accordance with physician preference or after entry into an RCT [1, 2]. All revascularization procedures involved percutaneous transluminal angioplasty; bare-metal stents were deployed in all procedures apart from interventions performed in the 1980s and early 1990s [n = 20 (21.1%)]; no embolic protection devices were used.
Clinical endpoints
Predefined primary clinical endpoints for this study were:
Date of death.
Date of first cardiovascular event (CVE) after enrolment (acute coronary syndrome, myocardial infarction, new arrhythmias, pulmonary oedema, decompensated heart failure, cerebrovascular accident and transient ischaemic attack).
Date of reaching end-stage kidney disease (ESKD), defined as the earliest of the following events: initiation of RRT (including renal transplantation) or eGFR <10 mL/min/1.73 m2, the average eGFR at which RRT is started in the UK [27].
A composite endpoint of the first of any of the above events.
Statistical analysis
Patients with missing baseline data were excluded. Baseline characteristics and eGFR slope were compared between control and high-risk patients, and between high-risk revascularized and high-risk non-revascularized patients. Non-parametrically distributed continuous data are presented as median (IQR). The chi-squared test was used to compare categorical data between the two groups, whereas the Mann–Whitney U-test was used for non-parametric continuous data. The rate of change of eGFR or eGFR slope from time zero to end of study was calculated from the slope of linear regression, excluding blood results taken during in-patient stays, patients who reached RRT and patients with <1 year follow-up or fewer than three data points. For revascularized patients, at least three data points pre-revascularization were used to calculate the eGFR slope. The number of clinical endpoints and unadjusted incidence rates per 100 patient-years were calculated manually. Kaplan–Meier curves were constructed and the log-rank test used to compare event rates between groups. Survival analyses were performed using the Cox proportional hazards model to determine HRs and 95% CIs for the effect of individual high-risk features, bilateral renal artery disease, proteinuria <1 g/day and revascularization on clinical endpoints. These analyses were adjusted for related comorbidities, age, baseline proteinuria and eGFR. ESKD and CVE endpoints were also adjusted for death in survival analyses. Data analyses were performed using SPSS (version 22.0) and a P < 0.05 was considered statistically significant.
RESULTS
Patient characteristics
Hospital records for 872 patients were screened; 593 (68%) patients were excluded, as they did not have severe RAS or were not candidates for revascularization [bilateral <70% RAS (n = 435), unilateral occlusion and contralateral <70% RAS (n = 142), bilateral occlusion (n = 16)]. Of the patients, 4 were excluded due to presumed diabetic nephropathy and 12 due to missing baseline data [eGFR (n = 1), proteinuria (n = 8), blood pressure (n = 3)]. This gave a study population of 263 patients. One hundred and twenty-seven patients (14.6% of 872) met criteria for the ‘high-risk’ category; 44 (5.1%) presented with FPE, 65 (7.5%) presented with severe hypertension, 61 (7.0%) had rapidly deteriorating renal function and 47 (5.4%) had more than one high-risk presentation. One hundred and thirty-six patients (15.6%) were designated as ‘control’ (≥70% unilateral or bilateral RAS but no high-risk clinical presentation, Figure 1). Of the study population, 75 had bilateral ≥70% RAS (41 high-risk patients, 34 controls) and 189 had proteinuria <1 g/day at baseline (99 high-risk patients, 90 controls). Fifty-five high-risk patients (43.3%) were revascularized compared with 40 (29.4%) control patients (P = 0.019, Table 1). Median follow-up time was 58.4 months (IQR 25.4–97.3) for the whole study population.
Comparison of baseline characteristics and eGFR slope between control and high-risk patients and between high-risk revascularized and high-risk non-revascularized patients
| Overall study population | Control | Combined high-riska | Control | Combined high-riska | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| (n = 263) | (n = 136) | (n = 127) | P | Non- revascularized (n = 96) | Revascularized (n = 40) | P | Non- revascularized (n = 76) | Revascularized (n = 55) | P | |
| Age (years) [median (IQR)] | 72.5 (66.8–77.4) | 72.3 (67.1–77.7) | 72.6 (65.6–76.6) | 0.5 | 72.9 (67.2–78.6) | 70.7 (66.6–75.8) | 0.1 | 74.0 (67.4–78.2) | 69.2 (64.7–75.5) | 0.02 |
| Male [n (%)] | 144 (54.8) | 77 (56.6) | 67 (52.8) | 0.5 | 56 (58.3) | 21 (52.5) | 0.5 | 41 (56.9) | 26 (47.3) | 0.3 |
| RAS ≥70% unilateral [n (%)] | 185 (70.3) | 99 (72.8) | 86 (67.7) | 0.4 | 76 (79.2) | 23 (57.5) | 0.01 | 56 (77.8) | 30 (54.5) | 0.006 |
| RAS ≥70% bilateral [n (%)] | 75 (28.5) | 34 (25.0) | 41 (32.3) | 0.2 | 17 (17.7) | 17 (42.5) | 0.002 | 16 (22.2) | 25 (45.5) | 0.006 |
| Patency score [median (IQR)] | 70.0 (40.0–115.0) | 80.0 (50.0–110.0) | 70.0 (40.0–115.0) | 0.4 | 90.0 (57.0–113.8) | 60.0 (20.0–110.0) | 0.02 | 82 (50.0–118.8) | 50.0 (30.0–110.0) | 0.03 |
| SBP (mmHg) [median (IQR)] | 155.0 (134.0–180.0) | 148.0 (130.0–164.3) | 165.0 (147.0–190.0) | <0.0005 | 145.0 (129.3–159.0) | 150.0 (132.3–170.0) | 0.2 | 164.0 (147.8–185.0) | 170.0 (144.0–194.0) | 0.2 |
| DBP (mmHg) [median (IQR)] | 80.0 (69.0–88.0) | 78 (68.3–85.0) | 80.0 (69.0–90.0) | 0.1 | 75.0 (65.0–85.8) | 80.0 (75.0–85.0) | 0.1 | 76.8 (65.5–88.8) | 80.0 (72.0–94.0) | 0.07 |
| MAP (mmHg) [median (IQR)] | 103.3 (92.7–115.3) | 99.8 (90.2–111.8) | 106.7 (96.7–123.0) | <0.0005 | 98.2 (89.0–110.0) | 103.2 (96.1–113.3) | 0.07 | 103.7 (96.7–117.2) | 112.0 (96.7–126.7) | 0.09 |
| Macrovascular disease [n (%)] | 203 (77.2) | 101 (74.3) | 102 (80.3) | 0.2 | 72 (75.0) | 29 (72.5) | 0.8 | 55 (76.4) | 47 (85.5) | 0.2 |
| Congestive heart failure [n (%)] | 57 (21.7) | 15 (11.0) | 42 (33.1) | <0.0005 | 10 (10.4) | 5 (12.5) | 0.7 | 22 (30.6) | 20 (36.4) | 0.5 |
| Flash pulmonary edema [n (%)] | 44 (16.7) | – | 44 (34.6) | – | – | – | – | 23 (31.9) | 21 (38.2) | 0.5 |
| Diabetes [n (%)] | 75 (28.5) | 27 (19.9) | 48 (37.8) | 0.001 | 21 (21.9) | 6 (15.0) | 0.4 | 29 (40.3) | 19 (34.5) | 0.5 |
| Renin angiotensin blockade [n (%)] | 144 (54.8) | 67 (49.3) | 77 (60.6) | 0.06 | 49 (51.0) | 18 (45.0) | 0.5 | 44 (61.1) | 33 (60.0) | 0.9 |
| Beta blocker [n (%)] | 107 (40.7) | 52 (38.2) | 55 (43.3) | 0.4 | 36 (37.5) | 16 (40.0) | 0.8 | 27 (37.5) | 28 (50.9) | 0.1 |
| Calcium channel blocker [n (%)] | 162 (61.6) | 85 (62.5) | 77 (60.6) | 0.8 | 60 (62.5) | 25 (62.5) | 1.00 | 46 (63.9) | 31 (56.4) | 0.4 |
| Three or more BP agents [n (%)] | 143 (54.4) | 51 (37.5) | 92 (72.4) | <0.0005 | 38 (39.6) | 13 (32.5) | 0.4 | 54 (75.0) | 38 (69.1) | 0.5 |
| Aspirin [n (%)] | 152 (57.8) | 74 (54.4) | 78 (61.4) | 0.3 | 53 (55.2) | 21 (52.5) | 0.8 | 42 (58.3) | 36 (65.5) | 0.4 |
| Statin [n (%)] | 167 (63.5) | 79 (58.1) | 88 (69.3) | 0.06 | 58 (60.4) | 21 (52.5) | 0.4 | 52 (72.2) | 36 (65.5) | 0.4 |
| Proteinuria (g/day) [median (IQR)] | 0.4 (0.1–1.1) | 0.3 (0.1–1.3) | 0.4 (0.2–0.9) | 0.9 | 0.4 (0.1–1.3) | 0.3 (0.1–1.2) | 0.5 | 0.4 (0.2–0.9) | 0.4 (0.1–1.0) | 0.5 |
| eGFR (mL/min/1.73 m2)a [median (IQR)] | 29.5 (20.4–41.3) | 28.5 (20.5–37.8) | 31.1 (20.3–44.5) | 0.1 | 28.5 (17.8–38.2) | 29.7 (20.9–37.6) | 0.7 | 33.3 (20.7–44.8) | 29.9 (18.6–43.5) | 0.4 |
| Revascularized [n (%)] | 95 (36.1) | 40 (29.4) | 55 (43.3) | 0.02 | – | – | – | – | – | |
| eGFR slope (mL/min/1.73 m2/year)b [median (IQR)] | −0.8 (−3.6 to 1.6)d | 0.5 (−0.8 to 4.9)e | −3.4 (−9.4 to − 0.6)f | <0.0005 | 0.4 (−0.9 to 2.5)g | 6.9 (−0.3 – 20.0)h | 0.008 | – | – | – |
| Overall study population | Control | Combined high-riska | Control | Combined high-riska | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| (n = 263) | (n = 136) | (n = 127) | P | Non- revascularized (n = 96) | Revascularized (n = 40) | P | Non- revascularized (n = 76) | Revascularized (n = 55) | P | |
| Age (years) [median (IQR)] | 72.5 (66.8–77.4) | 72.3 (67.1–77.7) | 72.6 (65.6–76.6) | 0.5 | 72.9 (67.2–78.6) | 70.7 (66.6–75.8) | 0.1 | 74.0 (67.4–78.2) | 69.2 (64.7–75.5) | 0.02 |
| Male [n (%)] | 144 (54.8) | 77 (56.6) | 67 (52.8) | 0.5 | 56 (58.3) | 21 (52.5) | 0.5 | 41 (56.9) | 26 (47.3) | 0.3 |
| RAS ≥70% unilateral [n (%)] | 185 (70.3) | 99 (72.8) | 86 (67.7) | 0.4 | 76 (79.2) | 23 (57.5) | 0.01 | 56 (77.8) | 30 (54.5) | 0.006 |
| RAS ≥70% bilateral [n (%)] | 75 (28.5) | 34 (25.0) | 41 (32.3) | 0.2 | 17 (17.7) | 17 (42.5) | 0.002 | 16 (22.2) | 25 (45.5) | 0.006 |
| Patency score [median (IQR)] | 70.0 (40.0–115.0) | 80.0 (50.0–110.0) | 70.0 (40.0–115.0) | 0.4 | 90.0 (57.0–113.8) | 60.0 (20.0–110.0) | 0.02 | 82 (50.0–118.8) | 50.0 (30.0–110.0) | 0.03 |
| SBP (mmHg) [median (IQR)] | 155.0 (134.0–180.0) | 148.0 (130.0–164.3) | 165.0 (147.0–190.0) | <0.0005 | 145.0 (129.3–159.0) | 150.0 (132.3–170.0) | 0.2 | 164.0 (147.8–185.0) | 170.0 (144.0–194.0) | 0.2 |
| DBP (mmHg) [median (IQR)] | 80.0 (69.0–88.0) | 78 (68.3–85.0) | 80.0 (69.0–90.0) | 0.1 | 75.0 (65.0–85.8) | 80.0 (75.0–85.0) | 0.1 | 76.8 (65.5–88.8) | 80.0 (72.0–94.0) | 0.07 |
| MAP (mmHg) [median (IQR)] | 103.3 (92.7–115.3) | 99.8 (90.2–111.8) | 106.7 (96.7–123.0) | <0.0005 | 98.2 (89.0–110.0) | 103.2 (96.1–113.3) | 0.07 | 103.7 (96.7–117.2) | 112.0 (96.7–126.7) | 0.09 |
| Macrovascular disease [n (%)] | 203 (77.2) | 101 (74.3) | 102 (80.3) | 0.2 | 72 (75.0) | 29 (72.5) | 0.8 | 55 (76.4) | 47 (85.5) | 0.2 |
| Congestive heart failure [n (%)] | 57 (21.7) | 15 (11.0) | 42 (33.1) | <0.0005 | 10 (10.4) | 5 (12.5) | 0.7 | 22 (30.6) | 20 (36.4) | 0.5 |
| Flash pulmonary edema [n (%)] | 44 (16.7) | – | 44 (34.6) | – | – | – | – | 23 (31.9) | 21 (38.2) | 0.5 |
| Diabetes [n (%)] | 75 (28.5) | 27 (19.9) | 48 (37.8) | 0.001 | 21 (21.9) | 6 (15.0) | 0.4 | 29 (40.3) | 19 (34.5) | 0.5 |
| Renin angiotensin blockade [n (%)] | 144 (54.8) | 67 (49.3) | 77 (60.6) | 0.06 | 49 (51.0) | 18 (45.0) | 0.5 | 44 (61.1) | 33 (60.0) | 0.9 |
| Beta blocker [n (%)] | 107 (40.7) | 52 (38.2) | 55 (43.3) | 0.4 | 36 (37.5) | 16 (40.0) | 0.8 | 27 (37.5) | 28 (50.9) | 0.1 |
| Calcium channel blocker [n (%)] | 162 (61.6) | 85 (62.5) | 77 (60.6) | 0.8 | 60 (62.5) | 25 (62.5) | 1.00 | 46 (63.9) | 31 (56.4) | 0.4 |
| Three or more BP agents [n (%)] | 143 (54.4) | 51 (37.5) | 92 (72.4) | <0.0005 | 38 (39.6) | 13 (32.5) | 0.4 | 54 (75.0) | 38 (69.1) | 0.5 |
| Aspirin [n (%)] | 152 (57.8) | 74 (54.4) | 78 (61.4) | 0.3 | 53 (55.2) | 21 (52.5) | 0.8 | 42 (58.3) | 36 (65.5) | 0.4 |
| Statin [n (%)] | 167 (63.5) | 79 (58.1) | 88 (69.3) | 0.06 | 58 (60.4) | 21 (52.5) | 0.4 | 52 (72.2) | 36 (65.5) | 0.4 |
| Proteinuria (g/day) [median (IQR)] | 0.4 (0.1–1.1) | 0.3 (0.1–1.3) | 0.4 (0.2–0.9) | 0.9 | 0.4 (0.1–1.3) | 0.3 (0.1–1.2) | 0.5 | 0.4 (0.2–0.9) | 0.4 (0.1–1.0) | 0.5 |
| eGFR (mL/min/1.73 m2)a [median (IQR)] | 29.5 (20.4–41.3) | 28.5 (20.5–37.8) | 31.1 (20.3–44.5) | 0.1 | 28.5 (17.8–38.2) | 29.7 (20.9–37.6) | 0.7 | 33.3 (20.7–44.8) | 29.9 (18.6–43.5) | 0.4 |
| Revascularized [n (%)] | 95 (36.1) | 40 (29.4) | 55 (43.3) | 0.02 | – | – | – | – | – | |
| eGFR slope (mL/min/1.73 m2/year)b [median (IQR)] | −0.8 (−3.6 to 1.6)d | 0.5 (−0.8 to 4.9)e | −3.4 (−9.4 to − 0.6)f | <0.0005 | 0.4 (−0.9 to 2.5)g | 6.9 (−0.3 – 20.0)h | 0.008 | – | – | – |
BP, blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. Bold data indicates a statistically significant difference with a p value <0.05.
All patients with at least one of FPE, deteriorating renal function or severe hypertension.
Calculated by the CKD-EPI [21].
Calculated from the slope of linear regression, excluding blood results taken during in-patient stay, patients who were on RRT and patients with <1 year follow-up or less than three data points. For revascularized patients, at least three pre-revascularization serum creatinine values were entered into the analysis.
Number of patients who met criteria for eGFR slope calculation (n) = 206;
n = 96;
n = 110;
n = 78;
n = 18.
Comparison of baseline characteristics and eGFR slope between control and high-risk patients and between high-risk revascularized and high-risk non-revascularized patients
| Overall study population | Control | Combined high-riska | Control | Combined high-riska | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| (n = 263) | (n = 136) | (n = 127) | P | Non- revascularized (n = 96) | Revascularized (n = 40) | P | Non- revascularized (n = 76) | Revascularized (n = 55) | P | |
| Age (years) [median (IQR)] | 72.5 (66.8–77.4) | 72.3 (67.1–77.7) | 72.6 (65.6–76.6) | 0.5 | 72.9 (67.2–78.6) | 70.7 (66.6–75.8) | 0.1 | 74.0 (67.4–78.2) | 69.2 (64.7–75.5) | 0.02 |
| Male [n (%)] | 144 (54.8) | 77 (56.6) | 67 (52.8) | 0.5 | 56 (58.3) | 21 (52.5) | 0.5 | 41 (56.9) | 26 (47.3) | 0.3 |
| RAS ≥70% unilateral [n (%)] | 185 (70.3) | 99 (72.8) | 86 (67.7) | 0.4 | 76 (79.2) | 23 (57.5) | 0.01 | 56 (77.8) | 30 (54.5) | 0.006 |
| RAS ≥70% bilateral [n (%)] | 75 (28.5) | 34 (25.0) | 41 (32.3) | 0.2 | 17 (17.7) | 17 (42.5) | 0.002 | 16 (22.2) | 25 (45.5) | 0.006 |
| Patency score [median (IQR)] | 70.0 (40.0–115.0) | 80.0 (50.0–110.0) | 70.0 (40.0–115.0) | 0.4 | 90.0 (57.0–113.8) | 60.0 (20.0–110.0) | 0.02 | 82 (50.0–118.8) | 50.0 (30.0–110.0) | 0.03 |
| SBP (mmHg) [median (IQR)] | 155.0 (134.0–180.0) | 148.0 (130.0–164.3) | 165.0 (147.0–190.0) | <0.0005 | 145.0 (129.3–159.0) | 150.0 (132.3–170.0) | 0.2 | 164.0 (147.8–185.0) | 170.0 (144.0–194.0) | 0.2 |
| DBP (mmHg) [median (IQR)] | 80.0 (69.0–88.0) | 78 (68.3–85.0) | 80.0 (69.0–90.0) | 0.1 | 75.0 (65.0–85.8) | 80.0 (75.0–85.0) | 0.1 | 76.8 (65.5–88.8) | 80.0 (72.0–94.0) | 0.07 |
| MAP (mmHg) [median (IQR)] | 103.3 (92.7–115.3) | 99.8 (90.2–111.8) | 106.7 (96.7–123.0) | <0.0005 | 98.2 (89.0–110.0) | 103.2 (96.1–113.3) | 0.07 | 103.7 (96.7–117.2) | 112.0 (96.7–126.7) | 0.09 |
| Macrovascular disease [n (%)] | 203 (77.2) | 101 (74.3) | 102 (80.3) | 0.2 | 72 (75.0) | 29 (72.5) | 0.8 | 55 (76.4) | 47 (85.5) | 0.2 |
| Congestive heart failure [n (%)] | 57 (21.7) | 15 (11.0) | 42 (33.1) | <0.0005 | 10 (10.4) | 5 (12.5) | 0.7 | 22 (30.6) | 20 (36.4) | 0.5 |
| Flash pulmonary edema [n (%)] | 44 (16.7) | – | 44 (34.6) | – | – | – | – | 23 (31.9) | 21 (38.2) | 0.5 |
| Diabetes [n (%)] | 75 (28.5) | 27 (19.9) | 48 (37.8) | 0.001 | 21 (21.9) | 6 (15.0) | 0.4 | 29 (40.3) | 19 (34.5) | 0.5 |
| Renin angiotensin blockade [n (%)] | 144 (54.8) | 67 (49.3) | 77 (60.6) | 0.06 | 49 (51.0) | 18 (45.0) | 0.5 | 44 (61.1) | 33 (60.0) | 0.9 |
| Beta blocker [n (%)] | 107 (40.7) | 52 (38.2) | 55 (43.3) | 0.4 | 36 (37.5) | 16 (40.0) | 0.8 | 27 (37.5) | 28 (50.9) | 0.1 |
| Calcium channel blocker [n (%)] | 162 (61.6) | 85 (62.5) | 77 (60.6) | 0.8 | 60 (62.5) | 25 (62.5) | 1.00 | 46 (63.9) | 31 (56.4) | 0.4 |
| Three or more BP agents [n (%)] | 143 (54.4) | 51 (37.5) | 92 (72.4) | <0.0005 | 38 (39.6) | 13 (32.5) | 0.4 | 54 (75.0) | 38 (69.1) | 0.5 |
| Aspirin [n (%)] | 152 (57.8) | 74 (54.4) | 78 (61.4) | 0.3 | 53 (55.2) | 21 (52.5) | 0.8 | 42 (58.3) | 36 (65.5) | 0.4 |
| Statin [n (%)] | 167 (63.5) | 79 (58.1) | 88 (69.3) | 0.06 | 58 (60.4) | 21 (52.5) | 0.4 | 52 (72.2) | 36 (65.5) | 0.4 |
| Proteinuria (g/day) [median (IQR)] | 0.4 (0.1–1.1) | 0.3 (0.1–1.3) | 0.4 (0.2–0.9) | 0.9 | 0.4 (0.1–1.3) | 0.3 (0.1–1.2) | 0.5 | 0.4 (0.2–0.9) | 0.4 (0.1–1.0) | 0.5 |
| eGFR (mL/min/1.73 m2)a [median (IQR)] | 29.5 (20.4–41.3) | 28.5 (20.5–37.8) | 31.1 (20.3–44.5) | 0.1 | 28.5 (17.8–38.2) | 29.7 (20.9–37.6) | 0.7 | 33.3 (20.7–44.8) | 29.9 (18.6–43.5) | 0.4 |
| Revascularized [n (%)] | 95 (36.1) | 40 (29.4) | 55 (43.3) | 0.02 | – | – | – | – | – | |
| eGFR slope (mL/min/1.73 m2/year)b [median (IQR)] | −0.8 (−3.6 to 1.6)d | 0.5 (−0.8 to 4.9)e | −3.4 (−9.4 to − 0.6)f | <0.0005 | 0.4 (−0.9 to 2.5)g | 6.9 (−0.3 – 20.0)h | 0.008 | – | – | – |
| Overall study population | Control | Combined high-riska | Control | Combined high-riska | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| (n = 263) | (n = 136) | (n = 127) | P | Non- revascularized (n = 96) | Revascularized (n = 40) | P | Non- revascularized (n = 76) | Revascularized (n = 55) | P | |
| Age (years) [median (IQR)] | 72.5 (66.8–77.4) | 72.3 (67.1–77.7) | 72.6 (65.6–76.6) | 0.5 | 72.9 (67.2–78.6) | 70.7 (66.6–75.8) | 0.1 | 74.0 (67.4–78.2) | 69.2 (64.7–75.5) | 0.02 |
| Male [n (%)] | 144 (54.8) | 77 (56.6) | 67 (52.8) | 0.5 | 56 (58.3) | 21 (52.5) | 0.5 | 41 (56.9) | 26 (47.3) | 0.3 |
| RAS ≥70% unilateral [n (%)] | 185 (70.3) | 99 (72.8) | 86 (67.7) | 0.4 | 76 (79.2) | 23 (57.5) | 0.01 | 56 (77.8) | 30 (54.5) | 0.006 |
| RAS ≥70% bilateral [n (%)] | 75 (28.5) | 34 (25.0) | 41 (32.3) | 0.2 | 17 (17.7) | 17 (42.5) | 0.002 | 16 (22.2) | 25 (45.5) | 0.006 |
| Patency score [median (IQR)] | 70.0 (40.0–115.0) | 80.0 (50.0–110.0) | 70.0 (40.0–115.0) | 0.4 | 90.0 (57.0–113.8) | 60.0 (20.0–110.0) | 0.02 | 82 (50.0–118.8) | 50.0 (30.0–110.0) | 0.03 |
| SBP (mmHg) [median (IQR)] | 155.0 (134.0–180.0) | 148.0 (130.0–164.3) | 165.0 (147.0–190.0) | <0.0005 | 145.0 (129.3–159.0) | 150.0 (132.3–170.0) | 0.2 | 164.0 (147.8–185.0) | 170.0 (144.0–194.0) | 0.2 |
| DBP (mmHg) [median (IQR)] | 80.0 (69.0–88.0) | 78 (68.3–85.0) | 80.0 (69.0–90.0) | 0.1 | 75.0 (65.0–85.8) | 80.0 (75.0–85.0) | 0.1 | 76.8 (65.5–88.8) | 80.0 (72.0–94.0) | 0.07 |
| MAP (mmHg) [median (IQR)] | 103.3 (92.7–115.3) | 99.8 (90.2–111.8) | 106.7 (96.7–123.0) | <0.0005 | 98.2 (89.0–110.0) | 103.2 (96.1–113.3) | 0.07 | 103.7 (96.7–117.2) | 112.0 (96.7–126.7) | 0.09 |
| Macrovascular disease [n (%)] | 203 (77.2) | 101 (74.3) | 102 (80.3) | 0.2 | 72 (75.0) | 29 (72.5) | 0.8 | 55 (76.4) | 47 (85.5) | 0.2 |
| Congestive heart failure [n (%)] | 57 (21.7) | 15 (11.0) | 42 (33.1) | <0.0005 | 10 (10.4) | 5 (12.5) | 0.7 | 22 (30.6) | 20 (36.4) | 0.5 |
| Flash pulmonary edema [n (%)] | 44 (16.7) | – | 44 (34.6) | – | – | – | – | 23 (31.9) | 21 (38.2) | 0.5 |
| Diabetes [n (%)] | 75 (28.5) | 27 (19.9) | 48 (37.8) | 0.001 | 21 (21.9) | 6 (15.0) | 0.4 | 29 (40.3) | 19 (34.5) | 0.5 |
| Renin angiotensin blockade [n (%)] | 144 (54.8) | 67 (49.3) | 77 (60.6) | 0.06 | 49 (51.0) | 18 (45.0) | 0.5 | 44 (61.1) | 33 (60.0) | 0.9 |
| Beta blocker [n (%)] | 107 (40.7) | 52 (38.2) | 55 (43.3) | 0.4 | 36 (37.5) | 16 (40.0) | 0.8 | 27 (37.5) | 28 (50.9) | 0.1 |
| Calcium channel blocker [n (%)] | 162 (61.6) | 85 (62.5) | 77 (60.6) | 0.8 | 60 (62.5) | 25 (62.5) | 1.00 | 46 (63.9) | 31 (56.4) | 0.4 |
| Three or more BP agents [n (%)] | 143 (54.4) | 51 (37.5) | 92 (72.4) | <0.0005 | 38 (39.6) | 13 (32.5) | 0.4 | 54 (75.0) | 38 (69.1) | 0.5 |
| Aspirin [n (%)] | 152 (57.8) | 74 (54.4) | 78 (61.4) | 0.3 | 53 (55.2) | 21 (52.5) | 0.8 | 42 (58.3) | 36 (65.5) | 0.4 |
| Statin [n (%)] | 167 (63.5) | 79 (58.1) | 88 (69.3) | 0.06 | 58 (60.4) | 21 (52.5) | 0.4 | 52 (72.2) | 36 (65.5) | 0.4 |
| Proteinuria (g/day) [median (IQR)] | 0.4 (0.1–1.1) | 0.3 (0.1–1.3) | 0.4 (0.2–0.9) | 0.9 | 0.4 (0.1–1.3) | 0.3 (0.1–1.2) | 0.5 | 0.4 (0.2–0.9) | 0.4 (0.1–1.0) | 0.5 |
| eGFR (mL/min/1.73 m2)a [median (IQR)] | 29.5 (20.4–41.3) | 28.5 (20.5–37.8) | 31.1 (20.3–44.5) | 0.1 | 28.5 (17.8–38.2) | 29.7 (20.9–37.6) | 0.7 | 33.3 (20.7–44.8) | 29.9 (18.6–43.5) | 0.4 |
| Revascularized [n (%)] | 95 (36.1) | 40 (29.4) | 55 (43.3) | 0.02 | – | – | – | – | – | |
| eGFR slope (mL/min/1.73 m2/year)b [median (IQR)] | −0.8 (−3.6 to 1.6)d | 0.5 (−0.8 to 4.9)e | −3.4 (−9.4 to − 0.6)f | <0.0005 | 0.4 (−0.9 to 2.5)g | 6.9 (−0.3 – 20.0)h | 0.008 | – | – | – |
BP, blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. Bold data indicates a statistically significant difference with a p value <0.05.
All patients with at least one of FPE, deteriorating renal function or severe hypertension.
Calculated by the CKD-EPI [21].
Calculated from the slope of linear regression, excluding blood results taken during in-patient stay, patients who were on RRT and patients with <1 year follow-up or less than three data points. For revascularized patients, at least three pre-revascularization serum creatinine values were entered into the analysis.
Number of patients who met criteria for eGFR slope calculation (n) = 206;
n = 96;
n = 110;
n = 78;
n = 18.
Flowchart illustrating selection of study population.
The high-risk and control groups were well matched for age, gender, patency score, bilateral disease, eGFR and proteinuria. However, high-risk patients were more likely to have diabetes (37.8% versus 19.9%, P = 0.001) and CHF (33.1% versus 11.0%, P < 0.0005) (Table 1). As expected, high-risk patients had higher blood pressure, and a greater proportion were receiving three or more anti-hypertensive agents. Revascularized patients had more severe anatomical stenosis than non-revascularized patients in both the high-risk and control groups. Revascularized control patients had a higher rate of loss of eGFR than non-revascularized controls, whereas revascularized high-risk patients were younger than those treated medically (69.2 versus 74.0 years, P = 0.02) (Table 1). Similar trends were noticed when examining the baseline characteristics for each individual high-risk presentation (Supplementary Table S1).
Impact of high-risk features, bilateral renal artery disease and baseline proteinuria on clinical endpoints
Overall annual mortality was 12.8% for control and 12.4% for high-risk patients, with ESKD occurring in 3.7 and 3.6%, and CVE in 7.7 and 12.0%, per year, respectively (Table 2). Development of ESKD was overall low (2.9% per year) in patients with <1 g/day of proteinuria. Supplementary Table S2 shows absolute patient numbers for each endpoint. An adjusted analysis showed that there was an increased risk for all four end points in patients with bilateral disease, and for every g/day increase in baseline proteinuria within the overall study population, and in high-risk patients presenting with rapidly deteriorating renal function (Table 3). Presentation with FPE significantly increased the risk for the composite endpoint [HR 1.54 (95% CI 1.04–2.30), P = 0.03] while patients with severe hypertension at time of diagnosis had a reduced hazard ratio for death [HR 0.69 (95% CI 0.48–0.99), P = 0.04] when compared with patients without these clinical presentations (Table 3).
Incidence rate per 100 patient-years of clinical endpoints in study population
| Control | Combined high-riska | Proteinuria <1 g/day | Bilateral ≥70% RAS | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| All (n = 136) | Non- revascularized (n = 96) | Revascularized (n = 40) | All (n = 127) | Non- revascularized (n = 72) | Revascularized (n = 55) | All (n = 189) | Non- revascularized (n = 1191) | Revascularized (n = 70) | All (n = 75) | Non- revascularized (n = 33) | Revascularized (n = 42) | |
| Died | 12.8 | 14.0 | 10.5 | 12.4 | 15.1 | 9.8 | 12.3 | 13.9 | 10.1 | 13.9 | 22.5 | 10.4 |
| ESKD | 3.7 | 3.2 | 4.6 | 3.6 | 4.4 | 2.8 | 2.9 | 2.4 | 3.5 | 5.0 | 8.3 | 3.8 |
| CVE | 7.7 | 7.1 | 8.8 | 12.0 | 14.9 | 9.5 | 9.2 | 9.9 | 8.4 | 10.5 | 15.4 | 8.5 |
| Any | 18.6 | 19.3 | 17.4 | 22.7 | 27.1 | 17.7 | 19.4 | 21.3 | 17.0 | 23.7 | 37.8 | 17.9 |
| Control | Combined high-riska | Proteinuria <1 g/day | Bilateral ≥70% RAS | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| All (n = 136) | Non- revascularized (n = 96) | Revascularized (n = 40) | All (n = 127) | Non- revascularized (n = 72) | Revascularized (n = 55) | All (n = 189) | Non- revascularized (n = 1191) | Revascularized (n = 70) | All (n = 75) | Non- revascularized (n = 33) | Revascularized (n = 42) | |
| Died | 12.8 | 14.0 | 10.5 | 12.4 | 15.1 | 9.8 | 12.3 | 13.9 | 10.1 | 13.9 | 22.5 | 10.4 |
| ESKD | 3.7 | 3.2 | 4.6 | 3.6 | 4.4 | 2.8 | 2.9 | 2.4 | 3.5 | 5.0 | 8.3 | 3.8 |
| CVE | 7.7 | 7.1 | 8.8 | 12.0 | 14.9 | 9.5 | 9.2 | 9.9 | 8.4 | 10.5 | 15.4 | 8.5 |
| Any | 18.6 | 19.3 | 17.4 | 22.7 | 27.1 | 17.7 | 19.4 | 21.3 | 17.0 | 23.7 | 37.8 | 17.9 |
All patients with at least one of FPE, deteriorating renal function or severe hypertension.
Incidence rate per 100 patient-years of clinical endpoints in study population
| Control | Combined high-riska | Proteinuria <1 g/day | Bilateral ≥70% RAS | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| All (n = 136) | Non- revascularized (n = 96) | Revascularized (n = 40) | All (n = 127) | Non- revascularized (n = 72) | Revascularized (n = 55) | All (n = 189) | Non- revascularized (n = 1191) | Revascularized (n = 70) | All (n = 75) | Non- revascularized (n = 33) | Revascularized (n = 42) | |
| Died | 12.8 | 14.0 | 10.5 | 12.4 | 15.1 | 9.8 | 12.3 | 13.9 | 10.1 | 13.9 | 22.5 | 10.4 |
| ESKD | 3.7 | 3.2 | 4.6 | 3.6 | 4.4 | 2.8 | 2.9 | 2.4 | 3.5 | 5.0 | 8.3 | 3.8 |
| CVE | 7.7 | 7.1 | 8.8 | 12.0 | 14.9 | 9.5 | 9.2 | 9.9 | 8.4 | 10.5 | 15.4 | 8.5 |
| Any | 18.6 | 19.3 | 17.4 | 22.7 | 27.1 | 17.7 | 19.4 | 21.3 | 17.0 | 23.7 | 37.8 | 17.9 |
| Control | Combined high-riska | Proteinuria <1 g/day | Bilateral ≥70% RAS | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| All (n = 136) | Non- revascularized (n = 96) | Revascularized (n = 40) | All (n = 127) | Non- revascularized (n = 72) | Revascularized (n = 55) | All (n = 189) | Non- revascularized (n = 1191) | Revascularized (n = 70) | All (n = 75) | Non- revascularized (n = 33) | Revascularized (n = 42) | |
| Died | 12.8 | 14.0 | 10.5 | 12.4 | 15.1 | 9.8 | 12.3 | 13.9 | 10.1 | 13.9 | 22.5 | 10.4 |
| ESKD | 3.7 | 3.2 | 4.6 | 3.6 | 4.4 | 2.8 | 2.9 | 2.4 | 3.5 | 5.0 | 8.3 | 3.8 |
| CVE | 7.7 | 7.1 | 8.8 | 12.0 | 14.9 | 9.5 | 9.2 | 9.9 | 8.4 | 10.5 | 15.4 | 8.5 |
| Any | 18.6 | 19.3 | 17.4 | 22.7 | 27.1 | 17.7 | 19.4 | 21.3 | 17.0 | 23.7 | 37.8 | 17.9 |
All patients with at least one of FPE, deteriorating renal function or severe hypertension.
Effect of high-risk features, bilateral renal artery disease and proteinuria on clinical endpoints in study population (n = 275)
| FPEa | Severe hypertensionb | Deteriorating renal functionc | Bilateral ≥70% RASd | Baseline proteinuria (g/day)e,f | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| HR | P | HR | P | HR | P | HR | P | HR | P | |
| Death | 1.54 (1.01–2.36) | 0.05 | 0.69 (0.48–0.99) | 0.04 | 1.74 (1.21–2.51) | 0.003 | 1.35 (0.94–1.93) | 0.1 | 1.27 (1.06–1.52) | 0.01 |
| ESKDg | 1.37 (0.90–2.07) | 0.1 | 0.71 (0.50–1.01) | 0.06 | 1.90 (1.32–2.74) | 0.001 | 1.64 (1.15–2.33) | 0.006 | 1.36 (1.14–1.63) | 0.001 |
| CVEg | 1.47 (0.98–2.21) | 0.06 | 0.83 (0.60–1.16) | 0.3 | 1.93 (1.36–2.75) | <0.0005 | 1.48 (1.06–2.08) | 0.02 | 1.49 (1.21–1.83) | <0.0005 |
| Any | 1.54 (1.04–2.30) | 0.03 | 0.84 (0.61–1.16) | 0.3 | 1.91 (1.35–2.71) | <0.0005 | 1.58 (1.13–2.21) | 0.008 | 1.56 (1.27–1.91) | <0.0005 |
| FPEa | Severe hypertensionb | Deteriorating renal functionc | Bilateral ≥70% RASd | Baseline proteinuria (g/day)e,f | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| HR | P | HR | P | HR | P | HR | P | HR | P | |
| Death | 1.54 (1.01–2.36) | 0.05 | 0.69 (0.48–0.99) | 0.04 | 1.74 (1.21–2.51) | 0.003 | 1.35 (0.94–1.93) | 0.1 | 1.27 (1.06–1.52) | 0.01 |
| ESKDg | 1.37 (0.90–2.07) | 0.1 | 0.71 (0.50–1.01) | 0.06 | 1.90 (1.32–2.74) | 0.001 | 1.64 (1.15–2.33) | 0.006 | 1.36 (1.14–1.63) | 0.001 |
| CVEg | 1.47 (0.98–2.21) | 0.06 | 0.83 (0.60–1.16) | 0.3 | 1.93 (1.36–2.75) | <0.0005 | 1.48 (1.06–2.08) | 0.02 | 1.49 (1.21–1.83) | <0.0005 |
| Any | 1.54 (1.04–2.30) | 0.03 | 0.84 (0.61–1.16) | 0.3 | 1.91 (1.35–2.71) | <0.0005 | 1.58 (1.13–2.21) | 0.008 | 1.56 (1.27–1.91) | <0.0005 |
Bold data indicates a statistically significant difference with a p value <0.05.
Adjusted for severe hypertension, deteriorating renal function, bilateral disease, age, diabetes, baseline proteinuria, eGFR and revascularization.
Adjusted for FPE, deteriorating renal function, bilateral disease, age, diabetes, baseline proteinuria, eGFR and revascularization.
Adjusted for FPE, severe hypertension, bilateral disease, age, diabetes, baseline proteinuria, eGFR and revascularization.
Adjusted for FPE, severe hypertension, deteriorating renal function, age, diabetes, baseline proteinuria, eGFR and revascularization.
Adjusted for FPE, severe hypertension, deteriorating renal function, bilateral disease, age, diabetes, eGFR and revascularization.
Hazard ratio calculated for every 1 g/day increase in baseline proteinuria.
Adjusted for death.
Effect of high-risk features, bilateral renal artery disease and proteinuria on clinical endpoints in study population (n = 275)
| FPEa | Severe hypertensionb | Deteriorating renal functionc | Bilateral ≥70% RASd | Baseline proteinuria (g/day)e,f | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| HR | P | HR | P | HR | P | HR | P | HR | P | |
| Death | 1.54 (1.01–2.36) | 0.05 | 0.69 (0.48–0.99) | 0.04 | 1.74 (1.21–2.51) | 0.003 | 1.35 (0.94–1.93) | 0.1 | 1.27 (1.06–1.52) | 0.01 |
| ESKDg | 1.37 (0.90–2.07) | 0.1 | 0.71 (0.50–1.01) | 0.06 | 1.90 (1.32–2.74) | 0.001 | 1.64 (1.15–2.33) | 0.006 | 1.36 (1.14–1.63) | 0.001 |
| CVEg | 1.47 (0.98–2.21) | 0.06 | 0.83 (0.60–1.16) | 0.3 | 1.93 (1.36–2.75) | <0.0005 | 1.48 (1.06–2.08) | 0.02 | 1.49 (1.21–1.83) | <0.0005 |
| Any | 1.54 (1.04–2.30) | 0.03 | 0.84 (0.61–1.16) | 0.3 | 1.91 (1.35–2.71) | <0.0005 | 1.58 (1.13–2.21) | 0.008 | 1.56 (1.27–1.91) | <0.0005 |
| FPEa | Severe hypertensionb | Deteriorating renal functionc | Bilateral ≥70% RASd | Baseline proteinuria (g/day)e,f | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| HR | P | HR | P | HR | P | HR | P | HR | P | |
| Death | 1.54 (1.01–2.36) | 0.05 | 0.69 (0.48–0.99) | 0.04 | 1.74 (1.21–2.51) | 0.003 | 1.35 (0.94–1.93) | 0.1 | 1.27 (1.06–1.52) | 0.01 |
| ESKDg | 1.37 (0.90–2.07) | 0.1 | 0.71 (0.50–1.01) | 0.06 | 1.90 (1.32–2.74) | 0.001 | 1.64 (1.15–2.33) | 0.006 | 1.36 (1.14–1.63) | 0.001 |
| CVEg | 1.47 (0.98–2.21) | 0.06 | 0.83 (0.60–1.16) | 0.3 | 1.93 (1.36–2.75) | <0.0005 | 1.48 (1.06–2.08) | 0.02 | 1.49 (1.21–1.83) | <0.0005 |
| Any | 1.54 (1.04–2.30) | 0.03 | 0.84 (0.61–1.16) | 0.3 | 1.91 (1.35–2.71) | <0.0005 | 1.58 (1.13–2.21) | 0.008 | 1.56 (1.27–1.91) | <0.0005 |
Bold data indicates a statistically significant difference with a p value <0.05.
Adjusted for severe hypertension, deteriorating renal function, bilateral disease, age, diabetes, baseline proteinuria, eGFR and revascularization.
Adjusted for FPE, deteriorating renal function, bilateral disease, age, diabetes, baseline proteinuria, eGFR and revascularization.
Adjusted for FPE, severe hypertension, bilateral disease, age, diabetes, baseline proteinuria, eGFR and revascularization.
Adjusted for FPE, severe hypertension, deteriorating renal function, age, diabetes, baseline proteinuria, eGFR and revascularization.
Adjusted for FPE, severe hypertension, deteriorating renal function, bilateral disease, age, diabetes, eGFR and revascularization.
Hazard ratio calculated for every 1 g/day increase in baseline proteinuria.
Adjusted for death.
Effect of revascularization on patients with high-risk features, bilateral renal artery disease, <1 g proteinuria at baseline and controls
Kaplan–Meier survival curves are shown for high-risk patients and controls in Figure 2, demonstrating the beneficial effect of revascularization in the former subgroup. Another Kaplan–Meier analysis also showed a benefit of revascularization on time to all outcomes in control patients with bilateral ≥70% RAS, but revascularization was only significantly associated with reduced time to CVE in high-risk patients with <1 g proteinuria (Supplementary Table S3).
(A)–(H) Kaplan–Meier curves showing time to death for revascularized and non-revascularized combined high-risk (patients with at least one of FPE, deteriorating renal function or severe hypertension) and control patients.
On analysing the effect of revascularization in overall aggregated high-risk categories and control patients adjusted for age, comorbidities, number of anti-hypertensives, statin use, baseline proteinuria, eGFR and blood pressure control, revascularization was significantly associated with reduced risk of ESKD [HR 0.59 (95% CI 0.37–0.93), P = 0.02] in high-risk patients. When the effect of revascularization was analysed in the individual clinical phenotype subgroups, revascularization was non-significantly associated with reduced adjusted hazard ratios for adverse events in patients presenting with FPE and severe hypertension. In patients with rapidly declining renal function, revascularization was significantly associated with reduced risk of ESKD [HR 0.47 (95% CI 0.25–0.85), P = 0.01], CVE [HR 0.51 (95% CI 0.29–0.91), P = 0.02] and all combined events [HR 0.51 (95% CI 0.29–0.90), P = 0.02] (Table 4).
Effect of revascularization on clinical endpoints in control, overall high-risk and in specific high-risk clinical presentation groups
| Control (n = 136) | Combined high-riska (n = 127)b | FPE (n = 44)c | Severe hypertension (n = 65)c | Deteriorating renal function (n = 61)c | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| HR | P | HR | P | HR | P | HR | P | HR | P | |
| Death | 0.84 (0.52–1.37) | 0.5 | 0.69 (0.43–1.09) | 0.1 | 0.87 (0.43–1.75) | 0.7 | 0.51 (0.22–1.15) | 0.1 | 0.62 (0.34–1.14) | 0.1 |
| ESKDd | 0.86 (0.53–1.39) | 0.5 | 0.59 (0.37–0.93) | 0.02 | 0.89 (0.46–1.75) | 0.7 | 0.51 (0.23–1.11) | 0.09 | 0.47 (0.25–0.85) | 0.01 |
| CVEd | 0.96 (0.61–1.51) | 0.9 | 0.65 (0.42–1.00) | 0.05 | 0.87 (0.43–1.78) | 0.7 | 0.51 (0.25–1.05) | 0.07 | 0.51 (0.29–0.91) | 0.02 |
| Any | 1.00 (0.63–1.57) | 0.9 | 0.67 (0.44–1.02) | 0.06 | 0.95 (0.48–1.88) | 0.9 | 0.59 (0.30–1.18) | 0.1 | 0.51 (0.29–0.90) | 0.02 |
| Control (n = 136) | Combined high-riska (n = 127)b | FPE (n = 44)c | Severe hypertension (n = 65)c | Deteriorating renal function (n = 61)c | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| HR | P | HR | P | HR | P | HR | P | HR | P | |
| Death | 0.84 (0.52–1.37) | 0.5 | 0.69 (0.43–1.09) | 0.1 | 0.87 (0.43–1.75) | 0.7 | 0.51 (0.22–1.15) | 0.1 | 0.62 (0.34–1.14) | 0.1 |
| ESKDd | 0.86 (0.53–1.39) | 0.5 | 0.59 (0.37–0.93) | 0.02 | 0.89 (0.46–1.75) | 0.7 | 0.51 (0.23–1.11) | 0.09 | 0.47 (0.25–0.85) | 0.01 |
| CVEd | 0.96 (0.61–1.51) | 0.9 | 0.65 (0.42–1.00) | 0.05 | 0.87 (0.43–1.78) | 0.7 | 0.51 (0.25–1.05) | 0.07 | 0.51 (0.29–0.91) | 0.02 |
| Any | 1.00 (0.63–1.57) | 0.9 | 0.67 (0.44–1.02) | 0.06 | 0.95 (0.48–1.88) | 0.9 | 0.59 (0.30–1.18) | 0.1 | 0.51 (0.29–0.90) | 0.02 |
Bold data indicates a statistically significant difference with a p value <0.05.
All patients with at least one of FPE, deteriorating renal function or severe hypertension.
Adjusted for age, CHF, FPE, diabetes mellitus, more than three or more anti-hypertensive agents at baseline, statin, baseline proteinuria and eGFR, and mean arterial pressure (MAP).
Adjusted for age, baseline proteinuria, MAP and eGFR.
Adjusted for death.
Effect of revascularization on clinical endpoints in control, overall high-risk and in specific high-risk clinical presentation groups
| Control (n = 136) | Combined high-riska (n = 127)b | FPE (n = 44)c | Severe hypertension (n = 65)c | Deteriorating renal function (n = 61)c | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| HR | P | HR | P | HR | P | HR | P | HR | P | |
| Death | 0.84 (0.52–1.37) | 0.5 | 0.69 (0.43–1.09) | 0.1 | 0.87 (0.43–1.75) | 0.7 | 0.51 (0.22–1.15) | 0.1 | 0.62 (0.34–1.14) | 0.1 |
| ESKDd | 0.86 (0.53–1.39) | 0.5 | 0.59 (0.37–0.93) | 0.02 | 0.89 (0.46–1.75) | 0.7 | 0.51 (0.23–1.11) | 0.09 | 0.47 (0.25–0.85) | 0.01 |
| CVEd | 0.96 (0.61–1.51) | 0.9 | 0.65 (0.42–1.00) | 0.05 | 0.87 (0.43–1.78) | 0.7 | 0.51 (0.25–1.05) | 0.07 | 0.51 (0.29–0.91) | 0.02 |
| Any | 1.00 (0.63–1.57) | 0.9 | 0.67 (0.44–1.02) | 0.06 | 0.95 (0.48–1.88) | 0.9 | 0.59 (0.30–1.18) | 0.1 | 0.51 (0.29–0.90) | 0.02 |
| Control (n = 136) | Combined high-riska (n = 127)b | FPE (n = 44)c | Severe hypertension (n = 65)c | Deteriorating renal function (n = 61)c | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| HR | P | HR | P | HR | P | HR | P | HR | P | |
| Death | 0.84 (0.52–1.37) | 0.5 | 0.69 (0.43–1.09) | 0.1 | 0.87 (0.43–1.75) | 0.7 | 0.51 (0.22–1.15) | 0.1 | 0.62 (0.34–1.14) | 0.1 |
| ESKDd | 0.86 (0.53–1.39) | 0.5 | 0.59 (0.37–0.93) | 0.02 | 0.89 (0.46–1.75) | 0.7 | 0.51 (0.23–1.11) | 0.09 | 0.47 (0.25–0.85) | 0.01 |
| CVEd | 0.96 (0.61–1.51) | 0.9 | 0.65 (0.42–1.00) | 0.05 | 0.87 (0.43–1.78) | 0.7 | 0.51 (0.25–1.05) | 0.07 | 0.51 (0.29–0.91) | 0.02 |
| Any | 1.00 (0.63–1.57) | 0.9 | 0.67 (0.44–1.02) | 0.06 | 0.95 (0.48–1.88) | 0.9 | 0.59 (0.30–1.18) | 0.1 | 0.51 (0.29–0.90) | 0.02 |
Bold data indicates a statistically significant difference with a p value <0.05.
All patients with at least one of FPE, deteriorating renal function or severe hypertension.
Adjusted for age, CHF, FPE, diabetes mellitus, more than three or more anti-hypertensive agents at baseline, statin, baseline proteinuria and eGFR, and mean arterial pressure (MAP).
Adjusted for age, baseline proteinuria, MAP and eGFR.
Adjusted for death.
Revascularization was associated with reduced risk of progression to ESKD in high-risk patients with bilateral ≥70% RAS [HR 0.35 (95% CI 0.15–0.84), P = 0.02], but not in controls with the same degree of RAS. In patients with <1 g/day proteinuria at baseline and any high-risk clinical presentation, revascularization was associated with reduced risk of ESKD [HR 0.52 (95% CI 0.32–0.86), P = 0.01], CVE [HR 0.52 (95% CI 0.32–0.83), P = 0.006] and all combined events [HR 0.57 (95% CI 0.36–0.90), P = 0.02]. In high-risk patients with both bilateral ≥70% RAS and <1 g/day proteinuria at baseline, revascularization was significantly associated with reduced risk of ESKD [HR 0.38 (95% CI 0.16–0.88), P = 0.03] (Table 5). There was no association between revascularization and improved outcomes in patients with ≥1 g/day baseline proteinuria (Supplementary Table S4).
Effect of revascularization on clinical endpoints in patients with bilateral renal artery disease and patients with proteinuria <1 g/day
| Bilateral ≥70% RAS (study population) (n = 75)a | Bilateral ≥70% RAS (high-risk)a (n = 41) | Bilateral ≥70% RAS (control)a (n = 34) | Proteinuria <1 g/day (study population)b (n = 189) | Proteinuria <1 g/day (high-risk)b (n = 99) | Proteinuria <1 g/day (control)b (n = 90) | Bilateral ≥70% RAS and proteinuria <1 g/day (study population) (n = 59)b | Bilateral ≥70% RAS and proteinuria <1 g/day (high-risk) (n = 36)b | Bilateral ≥70% RAS and proteinuria <1 g/day (control) (n = 23)b | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | |
| Death | 0.71 (0.38–1.32) | 0.3 | 0.59 (0.25–1.38) | 0.2 | 0.80 (0.30–2.13) | 0.6 | 0.76 (0.52–1.10) | 0.1 | 0.64 (0.38–1.05) | 0.08 | 0.87 (0.48–1.56) | 0.6 | 0.52 (0.28–0.99) | 0.05 | 0.56 (0.24–1.31) | 0.2 | 0.37 (0.12–1.19) | 0.09 |
| ESKDc | 0.53 (0.29–0.98) | 0.04 | 0.35 (0.15–0.84) | 0.02 | 0.72 (0.28–1.84) | 0.5 | 0.69 (0.48–0.99) | 0.04 | 0.52 (0.32–0.86) | 0.01 | 0.87 (0.48–1.57) | 0.6 | 0.46 (0.25–0.86) | 0.02 | 0.38 (0.16–0.88) | 0.03 | 0.50 (0.16–1.57) | 0.2 |
| CVEc | 0.55 (0.31–0.99) | 0.05 | 0.54 (0.24–1.20) | 0.1 | 0.40 (0.15–1.08) | 0.07 | 0.79 (0.56–1.12) | 0.2 | 0.52 (0.32–0.83) | 0.006 | 1.17 (0.68–2.00) | 0.6 | 0.46 (0.25–0.86) | 0.02 | 0.48 (0.22–1.07) | 0.07 | 0.35 (0.11–1.09) | 0.07 |
| Any | 0.60 (0.34–1.06) | 0.08 | 0.50 (0.23–1.10) | 0.08 | 0.51 (0.19–1.36) | 0.2 | 0.85 (0.61–1.20) | 0.4 | 0.57 (0.36–0.90) | 0.02 | 1.28 (0.75–2.19) | 0.4 | 0.53 (0.29–0.97) | 0.04 | 0.51 (0.23–1.10) | 0.09 | 0.50 (0.16–1.54) | 0.2 |
| Bilateral ≥70% RAS (study population) (n = 75)a | Bilateral ≥70% RAS (high-risk)a (n = 41) | Bilateral ≥70% RAS (control)a (n = 34) | Proteinuria <1 g/day (study population)b (n = 189) | Proteinuria <1 g/day (high-risk)b (n = 99) | Proteinuria <1 g/day (control)b (n = 90) | Bilateral ≥70% RAS and proteinuria <1 g/day (study population) (n = 59)b | Bilateral ≥70% RAS and proteinuria <1 g/day (high-risk) (n = 36)b | Bilateral ≥70% RAS and proteinuria <1 g/day (control) (n = 23)b | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | |
| Death | 0.71 (0.38–1.32) | 0.3 | 0.59 (0.25–1.38) | 0.2 | 0.80 (0.30–2.13) | 0.6 | 0.76 (0.52–1.10) | 0.1 | 0.64 (0.38–1.05) | 0.08 | 0.87 (0.48–1.56) | 0.6 | 0.52 (0.28–0.99) | 0.05 | 0.56 (0.24–1.31) | 0.2 | 0.37 (0.12–1.19) | 0.09 |
| ESKDc | 0.53 (0.29–0.98) | 0.04 | 0.35 (0.15–0.84) | 0.02 | 0.72 (0.28–1.84) | 0.5 | 0.69 (0.48–0.99) | 0.04 | 0.52 (0.32–0.86) | 0.01 | 0.87 (0.48–1.57) | 0.6 | 0.46 (0.25–0.86) | 0.02 | 0.38 (0.16–0.88) | 0.03 | 0.50 (0.16–1.57) | 0.2 |
| CVEc | 0.55 (0.31–0.99) | 0.05 | 0.54 (0.24–1.20) | 0.1 | 0.40 (0.15–1.08) | 0.07 | 0.79 (0.56–1.12) | 0.2 | 0.52 (0.32–0.83) | 0.006 | 1.17 (0.68–2.00) | 0.6 | 0.46 (0.25–0.86) | 0.02 | 0.48 (0.22–1.07) | 0.07 | 0.35 (0.11–1.09) | 0.07 |
| Any | 0.60 (0.34–1.06) | 0.08 | 0.50 (0.23–1.10) | 0.08 | 0.51 (0.19–1.36) | 0.2 | 0.85 (0.61–1.20) | 0.4 | 0.57 (0.36–0.90) | 0.02 | 1.28 (0.75–2.19) | 0.4 | 0.53 (0.29–0.97) | 0.04 | 0.51 (0.23–1.10) | 0.09 | 0.50 (0.16–1.54) | 0.2 |
Bold data indicates a statistically significant difference with a p value <0.05.
Adjusted for age, baseline proteinuria and eGFR.
Adjusted for age and baseline eGFR.
Adjusted for death.
Effect of revascularization on clinical endpoints in patients with bilateral renal artery disease and patients with proteinuria <1 g/day
| Bilateral ≥70% RAS (study population) (n = 75)a | Bilateral ≥70% RAS (high-risk)a (n = 41) | Bilateral ≥70% RAS (control)a (n = 34) | Proteinuria <1 g/day (study population)b (n = 189) | Proteinuria <1 g/day (high-risk)b (n = 99) | Proteinuria <1 g/day (control)b (n = 90) | Bilateral ≥70% RAS and proteinuria <1 g/day (study population) (n = 59)b | Bilateral ≥70% RAS and proteinuria <1 g/day (high-risk) (n = 36)b | Bilateral ≥70% RAS and proteinuria <1 g/day (control) (n = 23)b | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | |
| Death | 0.71 (0.38–1.32) | 0.3 | 0.59 (0.25–1.38) | 0.2 | 0.80 (0.30–2.13) | 0.6 | 0.76 (0.52–1.10) | 0.1 | 0.64 (0.38–1.05) | 0.08 | 0.87 (0.48–1.56) | 0.6 | 0.52 (0.28–0.99) | 0.05 | 0.56 (0.24–1.31) | 0.2 | 0.37 (0.12–1.19) | 0.09 |
| ESKDc | 0.53 (0.29–0.98) | 0.04 | 0.35 (0.15–0.84) | 0.02 | 0.72 (0.28–1.84) | 0.5 | 0.69 (0.48–0.99) | 0.04 | 0.52 (0.32–0.86) | 0.01 | 0.87 (0.48–1.57) | 0.6 | 0.46 (0.25–0.86) | 0.02 | 0.38 (0.16–0.88) | 0.03 | 0.50 (0.16–1.57) | 0.2 |
| CVEc | 0.55 (0.31–0.99) | 0.05 | 0.54 (0.24–1.20) | 0.1 | 0.40 (0.15–1.08) | 0.07 | 0.79 (0.56–1.12) | 0.2 | 0.52 (0.32–0.83) | 0.006 | 1.17 (0.68–2.00) | 0.6 | 0.46 (0.25–0.86) | 0.02 | 0.48 (0.22–1.07) | 0.07 | 0.35 (0.11–1.09) | 0.07 |
| Any | 0.60 (0.34–1.06) | 0.08 | 0.50 (0.23–1.10) | 0.08 | 0.51 (0.19–1.36) | 0.2 | 0.85 (0.61–1.20) | 0.4 | 0.57 (0.36–0.90) | 0.02 | 1.28 (0.75–2.19) | 0.4 | 0.53 (0.29–0.97) | 0.04 | 0.51 (0.23–1.10) | 0.09 | 0.50 (0.16–1.54) | 0.2 |
| Bilateral ≥70% RAS (study population) (n = 75)a | Bilateral ≥70% RAS (high-risk)a (n = 41) | Bilateral ≥70% RAS (control)a (n = 34) | Proteinuria <1 g/day (study population)b (n = 189) | Proteinuria <1 g/day (high-risk)b (n = 99) | Proteinuria <1 g/day (control)b (n = 90) | Bilateral ≥70% RAS and proteinuria <1 g/day (study population) (n = 59)b | Bilateral ≥70% RAS and proteinuria <1 g/day (high-risk) (n = 36)b | Bilateral ≥70% RAS and proteinuria <1 g/day (control) (n = 23)b | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | HR | P | |
| Death | 0.71 (0.38–1.32) | 0.3 | 0.59 (0.25–1.38) | 0.2 | 0.80 (0.30–2.13) | 0.6 | 0.76 (0.52–1.10) | 0.1 | 0.64 (0.38–1.05) | 0.08 | 0.87 (0.48–1.56) | 0.6 | 0.52 (0.28–0.99) | 0.05 | 0.56 (0.24–1.31) | 0.2 | 0.37 (0.12–1.19) | 0.09 |
| ESKDc | 0.53 (0.29–0.98) | 0.04 | 0.35 (0.15–0.84) | 0.02 | 0.72 (0.28–1.84) | 0.5 | 0.69 (0.48–0.99) | 0.04 | 0.52 (0.32–0.86) | 0.01 | 0.87 (0.48–1.57) | 0.6 | 0.46 (0.25–0.86) | 0.02 | 0.38 (0.16–0.88) | 0.03 | 0.50 (0.16–1.57) | 0.2 |
| CVEc | 0.55 (0.31–0.99) | 0.05 | 0.54 (0.24–1.20) | 0.1 | 0.40 (0.15–1.08) | 0.07 | 0.79 (0.56–1.12) | 0.2 | 0.52 (0.32–0.83) | 0.006 | 1.17 (0.68–2.00) | 0.6 | 0.46 (0.25–0.86) | 0.02 | 0.48 (0.22–1.07) | 0.07 | 0.35 (0.11–1.09) | 0.07 |
| Any | 0.60 (0.34–1.06) | 0.08 | 0.50 (0.23–1.10) | 0.08 | 0.51 (0.19–1.36) | 0.2 | 0.85 (0.61–1.20) | 0.4 | 0.57 (0.36–0.90) | 0.02 | 1.28 (0.75–2.19) | 0.4 | 0.53 (0.29–0.97) | 0.04 | 0.51 (0.23–1.10) | 0.09 | 0.50 (0.16–1.54) | 0.2 |
Bold data indicates a statistically significant difference with a p value <0.05.
Adjusted for age, baseline proteinuria and eGFR.
Adjusted for age and baseline eGFR.
Adjusted for death.
DISCUSSION
Our results concur with our previous finding that revascularization may confer benefit to patients with ‘high-risk’ clinical presentations [16]. Uniquely, we show here that even within this group, further stratification for likelihood of benefit can be achieved by considering bilateral severe RAS and low levels of proteinuria at time of diagnosis.
In patients with haemodynamically significant ARVD, activation of the renin–angiotensin system (RAAS) leads to secondary hypertension and triggers an inflammatory cascade that leads to renal parenchymal damage and loss of function [8, 28]. Patients are also at risk of developing cardiac disturbance syndromes such as acute decompensated heart failure or ischaemic events due to impaired pressure natriuresis. Observational studies have shown that timely revascularization can reduce activation of RAAS and improve renal perfusion, leading to reduction in arterial pressure, improvement in fluid overload and stabilization of the cardiac disturbance syndrome [8, 29].
Such patients have been under-represented in clinical trials; mortality in our study population was higher than in major clinical trials (12% per year compared with 4–8%) [1, 2]. This probably acted as a competing risk for progression to ESKD; the trajectory of eGFR decline in our overall study population is similar to that reported in age-matched ARVD and non-ARVD CKD cohorts, although the ‘high-risk’ subgroup had around a three-fold higher rate of eGFR loss per year [30, 31]. Also, in the Cardiovascular outcomes in renal atherosclerotic lesions (CORAL) study the mean eGFR of the patients was 59 mL/min, which was substantially higher than in our study (31 mL/min).
Accurate identification of haemodynamic significance is difficult in clinical practice. Selection of ‘high-risk’ patients needs to be based on both the ‘anatomical severity’ of ARVD and the clinical phenotype of the patient. The degree of cross-sectional stenosis correlates poorly with fractional flow reserve or translesional pressure gradients, and indeed, a lower cut-off of >50% on catheter angiography has been found to falsely identify haemodynamically significant stenosis in 38% of cases [32, 33]. We found no difference in patency score or bilateral disease between control and high-risk patients. In contrast to our earlier study [16], we have used ≥70% RAS as indicating severe stenosis in keeping with current recommendations [19]. We also increased the threshold for definition of uncontrolled or severe hypertension to reflect current guidance and focused on patients with a rate of negative eGFR slope below the 25th percentile for all ARVD patients within our database [24]. As a result of these ‘tighter’ selection criteria, only 15% of the total ARVD population met our definition of ‘high-risk’ compared with 28% reported in the earlier study, and a larger proportion of ‘high-risk’ patients in our study underwent revascularization (43% compared with 24%) [16].
Our results confirm that bilateral severe RAS is associated with an increased risk of adverse events [34], as are deteriorating renal function and greater baseline proteinuria. This highlights the complex interplay between intrarenal damage, haemodynamic compromise and overall atherosclerotic burden in determining clinical outcomes in ARVD [17, 34–36]. As in our earlier study, presentation with FPE increased the risk of adverse events, although the smaller numbers in the current study had an impact on the strength of the statistical association.
Severe hypertension was associated with reduced hazard ratios for all endpoints. Longitudinal change in blood pressure was not included in this analysis, hence successful response to medical therapy may account for improved long-term outcomes. Alternatively, this effect may reflect the J-shaped relationship that has been observed between lower blood pressures and adverse outcomes especially in higher risk patients [37].
Revascularization appears to reduce the risk of adverse outcomes in high-risk patients, but not in controls, despite the presence of more severe RAS and bilateral disease in the high-risk group. This survival benefit was predominantly in patients with rapidly deteriorating renal function. This finding is replicated elsewhere [1, 9, 10, 12, 37]. Although a small number of prospective, non-randomized studies have shown that revascularization may be appropriate in patients with severe hypertension, this has never been correlated to long-term hard outcomes [15, 38]. In contrast to our previous findings, revascularization was not statistically associated with improved outcomes in patients with FPE although hazard ratios were reduced, and this is probably due to sample size. We believe that revascularization should still be considered in patients presenting with FPE.
Our results suggest that revascularization is more frequently performed in patients with bilateral severe RAS, i.e. that clinicians may base revascularization decisions on anatomical stenosis severity. Revascularization may reduce the risk of both death and progression to ESKD in patients who have high-risk clinical presentation in addition to bilateral severe RAS, but not severe RAS alone. Consistent with this, one meta-analysis did not find any differences in response to revascularization between patients with unilateral or bilateral RAS [3], whereas a second meta-analysis found insufficient data to allow for subgroup analysis between unilateral and bilateral disease [4]. A small RCT did show that revascularization can improve blood pressure control in patients with bilateral >50% RAS and a diastolic blood pressure >95 mmHg [39].
The haemodynamic compromise triggered by ARVD leads to an inflammatory cascade culminating in renal microvascular remodelling and fibrosis. In this context, restoration of renal artery patency may fail to improve renal clearance [28, 40, 41]. We have used proteinuria as a surrogate marker of irreversible renal parenchymal injury, although proteinuria is also associated with general upregulation of systemic inflammation and vascular endothelial dysfunction [42, 43]. In keeping with our previous findings, we have shown that outcomes post-revascularization are better in patients with lower degrees of proteinuria at time of diagnosis, emphasizing the importance of timely revascularization before the development of irreversible parenchymal damage [18].
Although numbers were limited, there was reduced progression to ESKD in high-risk patients with both bilateral severe stenosis and <1 g/day proteinuria. These patients may represent an important subgroup with haemodynamically significant stenosis but preserved renal parenchyma. We have previously shown that kidneys with a high renal volume to GFR ratio functionally do better post-revascularization; these kidneys presumably have viable, ‘hibernating’ parenchyma [44]. Current research efforts are focusing on development of non-invasive magnetic-resonance-based techniques that can help characterize both the haemodynamic significance of a stenosis and the viability of the post-stenotic renal parenchyma [45].
The main limitation of this study is that it is retrospective, and that patients were not randomized to revascularization, hence selection bias and hidden confounders potentially affect the results. The study has included patients who were recruited over three decades. During this time interval, the approach to ARVD has evolved significantly. A larger proportion of patients are now established on multi-targeted medical therapy, whereas those with more cardiovascular comorbidities tend to be selectively referred for revascularization, potentially underestimating the benefit gained from revascularization [5]. Study patient numbers were small and this restricted the extent of adjusting within Cox regression models. The definitions used for some high-risk presentations are arbitrary and potentially imprecise. For example, the lack of uniform echocardiographic data did not permit accurate confirmation of FPE. Blood pressure was documented from office readings taken at the time of diagnosis, and medication dosage and longitudinal change were not included in the analyses. While RAS ≥70% was considered ‘severe’ stenosis for the purpose of this study in line with current recommendations [19], the actual haemodynamic significance of RAS was not evaluated or confirmed and the degree of stenosis was determined by a single observer and based on biplanar imaging studies only; it is known that the severity of RAS is frequently over-estimated on angiography [2].
Nonetheless, data were meticulously collected in a standardized manner on an annual basis from patient records throughout the three decades. The size of our overall study population, approaching 900 patients, has enabled an insightful analysis of patients that are under-represented in RCTs.
CONCLUSION
Our study confirms that FPE, rapidly deteriorating renal function, greater baseline proteinuria and severe bilateral renal artery disease are adverse prognostic features in patients with ARVD. We also provide further evidence that revascularization appears to be of benefit in high-risk patients, especially those presenting with rapidly deteriorating renal function and concurrent bilateral ≥70% RAS and/or <1 g/day baseline proteinuria.
SUPPLEMENTARY DATA
Supplementary data are available online at http://ndt.oxfordjournals.org.
CONFLICT OF INTEREST STATEMENT
None declared.
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