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. Author manuscript; available in PMC: 2017 Nov 1.
Published in final edited form as: Hypertension. 2016 Sep 19;68(5):1145–1152. doi: 10.1161/HYPERTENSIONAHA.116.07744

Relationship of Albuminuria and Renal Artery Stent Outcomes: Results from the Cardiovascular Outcomes with Renal Artery Lesions (CORAL) Randomized Clinical Trial

Timothy P Murphy 1, Christopher J Cooper 1, Karol M Pencina 1, Ralph D’Agostino 1, Joseph Massaro 1, Donald E Cutlip 1, Kenneth Jamerson 1, Alan H Matsumoto 1, William Henrich 1, Joseph I Shapiro 1, Katherine R Tuttle 1, David J Cohen 1, Michael Steffes 1, Qi Gao 1, D Christopher Metzger 1, William B Abernethy 1, Stephen C Textor 1, John Briguglio 1, Alan T Hirsch 1, Sheldon Tobe 1, Lance D Dworkin 1
PMCID: PMC5634521  NIHMSID: NIHMS810866  PMID: 27647847

Abstract

Randomized clinical trials have not shown an additional clinical benefit of renal artery stent placement over optimal medical therapy alone. However, studies of renal artery stent placement have not examined the relationship of albuminuria and treatment group outcomes.

The CORAL study is a prospective clinical trial of 947 participants with atherosclerotic renal artery stenosis randomized to optimal medical therapy (OMT) with or without renal artery stent which showed no treatment differences (35.8% and 35.1% event rate at mean 43 month follow-up). In a post-hoc analysis, the study population was stratified by the median baseline urine albumin/creatinine ratio (uACR)(n=826) and analyzed for the 5-year incidence of the primary endpoint (myocardial infarction, hospitalization for congestive heart failure, stroke, renal replacement therapy, progressive renal insufficiency, or cardiovascular- or kidney disease-related death), as well as for each component of the primary endpoint, and overall survival.

When baseline uACR was <= median (22.5 mg/g, n=413), renal artery stenting was associated with significantly better event-free survival from the primary composite endpoint (73% vs 59% at 5 years, p=.02), cardiovascular disease-related death (93% vs. 85%, p=<.01), progressive renal insufficiency (91% vs 77%, p=.03), and overall survival (89% vs. 76%, p=<.01), but not when baseline uACR was > median (n=413).

These data suggest that low albuminuria may indicate a potentially large subgroup of those with renal artery stenosis that could experience improved event-free and overall-survival after renal artery stent placement plus OMT compared with OMT alone. Further research is needed to confirm these preliminary observations.

Keywords: hypertension, kidney, hypertension, angioplasty and stenting, chronic kidney disease, atherosclerosis

Subject Codes: Stent, revascularization, high blood pressure, hypertension, atherosclerosis

Introduction

Prospective randomized clinical trials of treatment for renal artery stenosis have not shown an additional clinical benefit of stent placement over optimal medical therapy for either hypertension or chronic kidney disease1–6. Increased albuminuria is often present in patients with hypertension and/or chronic kidney disease7 and those with renal artery stenosis8, and is associated with an increased risk of adverse cardiovascular and renal events9. The impact of baseline microalbuminuria on cardiovascular, renal, and survival outcomes after renal artery revascularization is unknown. After Principal Component Analysis (PCA) revealed a high degree of variance in baseline urine albumin/creatinine ratios, we used data from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study4, a randomized multicenter clinical trial that examined renal artery stent placement for patients with renal artery stenosis and hypertension and/or chronic kidney disease, to examine whether the presence of baseline albuminuria had an effect on patient outcomes and stent treatment response.

Materials and Methods

This is a post-hoc analysis using data from the CORAL study4, a multicenter, two-arm randomized clinical trial that evaluated 931 patients with renal artery stenosis and either resistant hypertension or chronic kidney disease. There were two treatment groups in CORAL; optimal medical therapy (“medical therapy”) and optimal medical therapy plus direct stent revascularization (“stent”). Background medical therapy was based on published guidelines10, 11. Stent revascularization was done so that all renal artery stenoses >=60% were treated. The study primary endpoint was a composite of myocardial infarction, hospitalization for congestive heart failure, stroke, renal replacement therapy, progressive renal insufficiency (>=30% reduction in estimated glomerular filtration rate (eGFR) sustained at least 60 days), and cardiovascular- or kidney disease-related death4. The study was approved by all participating institution review boards and all study participants gave informed consent. The full study protocol, and a summary of changes, can be accessed at http://www.nejm.org/action/showSupplements?doi=10.1056%2FNEJMoa1310753&viewType=Popup&viewClass=Suppl.

Principal component analysis (PCA)12 of CORAL study data revealed baseline urine albumin/creatinine ratio (uACR) to be strongly associated with patient outcomes (see Supplemental Table S1). Therefore, CORAL participants were stratified according to their aggregate median uACR, which was 22.5 mg/g. The population was divided in two (n=413 in each group) by the median uACR because it was the simplest and most convenient way to test the relationship of baseline uACR with treatment outcomes, with Cohort 1 being those with baseline uACR<=22.5 mg/g, and Cohort those with baseline uACR>22.5 mg/g. Other analyses were also done to test the sensitivity of the results to varying thresholds of uACR. For example, the analysis was repeated after dividing the CORAL cohort was divided into deciles by baseline uACR. Also, we used a traditional uACR cut-point for microalbuminuria, 30 mg/g, to divide the CORAL cohort into two groups for analysis.

As our primary analysis, the duration of freedom from the primary composite endpoint was calculated by treatment group for both cohorts using Kaplan-Meier analysis, and compared using log-rank tests within each uACR stratum. Secondary analyses were performed for each component of the primary composite endpoint and for overall survival using similar methods. A test for interaction of the uACR cohort with the treatment group on time-to-primary-endpoint over the entire study was carried out using Cox proportional hazards regression with main effects of uACR stratum and treatment group, and the interaction effect of uACR-by-treatment outcomes

A generalized estimating equation analysis of variance was used to compare treatments with respect to systolic blood pressure over time within each uACR cohort. This was carried out in order to examine whether any reduction in endpoints by treatment group might be attributable to better systolic blood pressure control. Comparison of the number of antihypertensive medications at the last follow-up visit between treatment groups was done using ANOVA for both uACR cohorts, and the proportions taking ACE/ARB medications was compared using Chi-square tests. Baseline data were significantly skewed, so Spearman rank correlation was done to examine the relationship between eGFR and uACR for the entire population with baseline urine ACR. Interaction tests on race and sex in CORAL showed no treatment group interactions for these variables and sex and race subgroups were not examined in this retrospective analysis4. All p-values are two-sided; original study data were accessible by and all analyses were done by authors K.M.P., R.D., J.M., Q.G., and T.P.M., and performed using SAS v.9.1.3 (SAS Institute, Cary, NC).

In CORAL, urine albumin:creatinine ratios were measured at the Biochemistry Core Lab at the University of Minnesota, under the direction of one of the authors (M.S.). Spot urine albumin was measured using kit reagents on the ProSpec nephelometric analyzer (Siemens, Dade Behring GMBH, Marburg, Germany D-35041). The coefficient of variation for this measurement was 5.6% at the low value (mean concentration 14 mg/L), and is unlikely to result in significant misclassification. Creatinine was measured in urine by the Roche enzymatic method (Roche Diagnostics, Indianapolis, IN 46250) on a Roche Modular P Chemistry Analyzer (Roche Diagnostics Corporation), a method that is traceable to reference isotope dilution mass spectroscopy (IDMS) developed by the National Institute of Standards and Technology (NIST). The CORAL Study was registered on ClinicalTrials.gov on April 19, 2004 (identifier NCT00081731).

Results

There were 931 evaluable participants enrolled in CORAL between May 2005 and January 20104, and 826 had baseline uACR measured and were available for these analyses. (Recruitment in the original study was stopped after 947 participants were enrolled, which was 88% of projected enrollment, by the Data Safety and Monitoring Board. 16 participants from one site were excluded from analysis due to data integrity issues). The average age of the aggregate group (N=826) was 69.3+/−8.9 (s.d.) years; 50% were females; 283 (35%) had diabetes mellitus; and 244 (30%) were smokers (Table 1). In addition to higher uACR, In Cohort 2 had a higher incidence of primary endpoints during CORAL than Cohort 1 (180/413 (44%) vs. 110/413, (27%)). In Cohort 1, the medical group had more prevalent diabetes mellitus, cigarette smoking, and prior MI, but lower total cholesterol, higher HDL, less prior heart failure, and less global ischemia than the stent group. Cohort 2 had a higher prevalence of diabetes mellitus, lower eGFR, higher baseline systolic blood pressure (Table 1) than Cohort 1, but within that cohort baseline variables were similar between treatment groups, except more prevalent prior heart failure in the medical therapy group and higher baseline uACR in the stent group. One-hundred five (105) CORAL participants had missing baseline uACR values and were not included in these analyses; their baseline characteristics were similar to those without missing baseline uACR, and those without baseline uACR treated with stent had similar baseline characteristics as those treated with medical therapy alone except that those with missing data in the medical therapy group had higher prevalence of diabetes mellitus, cigarette smoking, prior MI, prior heart failure, and more global stenosis (Table 1). There were 356 CORAL participants with either moderately (uACR >=30<=300 mg/g) or severely (uACR >300 mg/g) increased albuminuria.

Table 1.

Baseline characteristics. Mean +/− standard deviation (for continuous data) or frequency (for proportional data) in each treatment group, (n), according to baseline urine albumin/creatinine ratio (<= or > the median value (22.5 mg/g)). In the low baseline uACR stratum, the medical therapy group had more prevalent diabetes mellitus, cigarette smoking, and prior MI, but lower total cholesterol, higher HDL, less prior heart failure, and less global ischemia. Patients without baseline uACR not included in the analyses are presented in the last two columns for comparison; their baseline characteristics are comparable to those without missing baseline uACR and also comparable between treatment groups, except that those with missing data in the medical therapy group had higher prevalence of diabetes mellitus, cigarette smoking, prior MI, prior heart failure, and more global stenosis. Their exclusion from the analyses therefore shows no evidence of biasing the analyses done for those with baseline uACR in favor of stent placement. “Global” ischemia = bilateral renal artery stenosis or unilateral stenosis in a uninephric patient.

Measure Cohort 1 (uACR <= 22.5 mg/g) Cohort 2 (uACR > 22.5 mg/g) uACR Not Available
Stent (N=199) Medical Therapy (N=214) Stent (N=209) Medical Therapy (N=204) Stent (N=51) Medical Therapy (N=54)
Age (years)
 Mean±SD (N) 68.72±9.13 (199) 68.22±9.48 (214) 70.11±9.02 (209) 70.40±8.11 (204) 68.35±11.33 (51) 66.81±9.21 (54)
 Range (Min,Max) (35.00,88.00) (37.00,89.00) (38.00,88.00) (46.00,87.00) (37.00,88.00) (45.00,87.00)
 Median (IQ Range) 70.00 (62.00 – 75.00) 69.00 (62.00 – 75.00) 71.00 (65.00 – 77.00) 71.00 (65.00 – 77.00) 71.00 (61.00 – 76.00) 66.00 (60.00 – 75.00)
Gender: Male 51.8% (103/199) 51.9% (111/214) 51.7% (108/209) 45.6% (93/204) 45.1% (23/51) 50.0% (27/54)
Race
 American Indian or Alaska Native 0.0% (0/199) 0.0% (0/214) 0.5% (1/209) 0.5% (1/204) 0.0% (0/51) 0.0% (0/54)
 Asian 0.5% (1/199) 3.3% (7/214) 1.4% (3/209) 0.0% (0/204) 2.0% (1/51) 0.0% (0/54)
 Black or African-American 6.0% (12/199) 5.6% (12/214) 7.7% (16/209) 8.3% (17/204) 7.8% (4/51) 7.4% (4/54)
 Native Hawaiian or Other Pacific Islander 0.5% (1/199) 0.0% (0/214) 0.0% (0/209) 0.0% (0/204) 0.0% (0/51) 3.7% (2/54)
 White 93.0% (185/199) 91.1% (195/214) 90.4% (189/209) 91.2% (186/204) 90.2% (46/51) 88.9% (48/54)
Systolic Blood Pressure (mmHg)
 Mean±SD (N) 145.20±21.92 (199) 145.03±21.66 (210) 154.93±23.34 (209) 157.29±23.55 (203) 147.11±23.40 (49) 145.25±19.03 (54)
 Range (Min,Max) (98.00,207.00) (105.33,218.67) (90.00,227.33) (93.33,219.33) (109.00,217.33) (99.33,200.00)
 Median (IQ Range) 144.00 (128.67 – 160.67) 143.17 (129.33 – 157.67) 154.67 (138.67 – 169.67) 155.33 (140.00 – 171.33) 150.00 (126.00 – 161.00) 146.00 (130.67 – 153.33)
Total Cholesterol
 Mean±SD (N) 164.65±42.93 (199) 162.79±41.34 (213) 163.63±41.65 (208) 162.09±44.18 (202) 163.04±55.21 (27) 158.54±30.19 (35)
 Range (Min,Max) (74.00,366.00) (86.00,302.00) (77.00,298.00) (78.00,406.00) (100.00,326.00) (100.00,233.00)
 Median (IQ Range) 158.00 (135.00 – 184.00) 155.00 (132.00 – 182.00) 158.50 (135.50 – 189.00) 155.00 (131.00 – 183.00) 160.00 (123.00 – 200.00) 156.00 (142.00 – 176.00)
HDL
 Mean±SD (N) 43.38±13.45 (197) 45.67±14.01 (214) 42.93±14.39 (208) 42.66±12.64 (202) 40.81±12.03 (27) 42.80±13.24 (35)
 Range (Min,Max) (19.00,93.00) (19.00,99.00) (15.00,94.00) (10.00,89.00) (22.00,72.00) (24.00,76.00)
 Median (IQ Range) 42.00 (33.00 – 49.00) 44.00 (36.00 – 54.00) 40.00 (33.00 – 49.00) 41.00 (34.00 – 50.00) 39.00 (31.00 – 46.00) 39.00 (33.00 – 50.00)
Statin usage 83.9% (167/199) 89.3% (191/214) 83.7% (175/209) 85.3% (174/204) 78.4% (40/51) 83.3% (45/54)
BMI
 Mean±SD (N) 28.14±4.80 (199) 28.21±6.04 (212) 28.22±5.36 (209) 29.10±5.51 (202) 28.61±6.61 (50) 28.75±4.93 (54)
 Range (Min,Max) (15.34,46.45) (16.14,61.90) (17.73,52.73) (16.56,46.62) (18.80,48.59) (18.04,45.72)
 Median (IQ Range) 27.53 (25.08 – 31.36) 27.21 (24.80 – 30.57) 27.25 (24.42 – 31.64) 28.71 (25.59 – 32.58) 27.71 (24.55 – 30.66) 28.25 (25.53 – 31.07)
Diabetes 25.6% (51/199) 27.1% (58/214) 41.3% (86/208) 43.1% (88/204) 22.0% (11/50) 29.6% (16/54)
Cigarette Smoking in the past year 28.4% (56/197) 37.4% (80/214) 27.1% (56/207) 25.7% (52/202) 30.0% (15/50) 35.8% (19/53)
Prior MI 25.4% (50/197) 30.5% (65/213) 28.2% (58/206) 29.1% (58/199) 24.0% (12/50) 32.7% (17/52)
Prior heart failure 10.1% (20/199) 8.9% (19/213) 14.4% (30/209) 19.6% (40/204) 10.0% (5/50) 22.6% (12/53)
Albumin Creatinine ratio
 Mean±SD (N) 10.65±5.23 (199) 10.34±5.40 (214) 454.42±1052.67 (209) 369.66±842.40 (204) N/A N/A
 Range (Min,Max) (1.47,22.22) (2.21,22.31) (22.92,7812.50) (22.68,5671.43)
 Median (IQ Range) 9.68 (6.45 – 14.81) 8.92 (5.66 – 14.52) 92.48 (43.15 – 282.95) 75.60 (35.73 – 213.12)
Core lab percent stenosis
 Mean±SD (N) 68.52±11.65 (186) 67.69±12.52 (130) 69.47±11.31 (200) 68.60±11.09 (138) 69.14±10.13 (47) 66.79±12.31 (36)
 Range (Min,Max) (20.80,95.41) (38.05,92.00) (34.33,100.00) (41.30,100.00) (46.26,91.21) (42.90,90.45)
 Median (IQ Range) 68.32 (59.89 – 76.55) 67.50 (57.23 – 77.90) 68.92 (61.09 – 78.14) 67.37 (60.38 – 76.31) 68.92 (60.46 – 74.77) 67.05 (57.86 – 77.67)
Global Ischemia 22.5% (43/191) 14.1% (19/135) 18.5% (38/205) 16.9% (24/142) 16.3% (8/49) 21.1% (8/38)
eGFR
 Mean±SD (N) 61.15±22.16 (199) 62.18±20.89 (214) 55.27±23.94 (208) 52.10±21.50 (202) 56.50±26.02 (29) 59.04±20.94 (38)
 Range (Min,Max) (18.09,132.60) (20.81,129.91) (15.97,133.59) (15.15,129.83) (25.59,148.74) (21.59,120.94)
 Median (IQ Range) 60.00 (42.63 – 75.91) 60.46 (45.67 – 75.68) 49.81 (38.52 – 68.56) 48.51 (34.85 – 65.33) 53.13 (40.39 – 63.48) 55.52 (46.23 – 71.41)
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Median of albumin/creatinine ratio among all available follow-up is 22.5.

There was a significant interaction between treatment group and uACR on the time to the composite primary endpoint (p=.02). Participants in Cohort 1 had significantly better freedom from the composite primary endpoint when treated with stent than medical therapy (5-year Kaplan-Meier estimates of 73% vs. 59%, p=.02, logrank test)(figure 1, supplemental figure S1), and the observed power for that comparison was 0.78. Freedom from cardiovascular death (93% vs. 85%, p=.009, supplemental figure S2), freedom from progressive renal insufficiency (91% vs. 77%, p=.03) (supplemental figure S3), and overall survival (89% vs. 76%, p=<.01)(supplemental figure S4) all favored stent over medical therapy in Cohort 1. None of the remaining components of the primary endpoint (myocardial infarction, hospitalization for congestive heart failure, stroke, renal replacement therapy) showed statistically significant differences in outcomes by treatment group in Cohort 1. There were no significant treatment group differences for either the primary composite endpoint or any of the individual components of the composite endpoint for Cohort 2 (figure 1; supplemental figures S1–S4).

Figure 1.

Figure 1

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Freedom from the primary composite endpoint* through 5 years of follow-up by treatment group and uACR cohort. For baseline uACR<=22.5 mg/g, the 5-year freedom from event for Stent vs. Medical groups was 73% vs. 59%, p=.02 (log-rank test). When baseline uACR > median, the 5-year freedom from event for Stent vs. Medical groups was 47% vs. 48%, p=.38 (log-rank test). *Primary composite endpoint = myocardial infarction, hospitalization for congestive heart failure, stroke, renal replacement therapy, progressive renal insufficiency, (>=30% reduction in estimated glomerular filtration rate (eGFR) sustained at least 60 days), or cardiovascular- or kidney disease-related death.

When the CORAL population was divided into ten deciles by baseline uACR, hazard ratios favored stent placement for all of the deciles below the median uACR value (22.5 mg/g), but only one was statistically significant (p=0.01)(figure 2). The decile with the highest hazard ratio that favored medical therapy was the one immediately above the median value (22.5–34.6 mg/dl). This had an impact on the sensitivity analysis using the conventional threshold for moderately increased albuminuria (30 mg/g); the analysis using the threshold of 30 mg/g showed an insignificant trend favoring stent placement for those with baseline uACR below that threshold (p=0.08).

Figure 2.

Figure 2

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Forest plot displaying treatment effects within uACR decile sub-groups.

For Cohort 1 there was no significant difference in systolic blood pressure over time between the two treatment groups (p=0.58)(figure 3A), but there was borderline significance for systolic blood pressure differences for Cohort 2 favoring stent (p=.052, figure 3B). The number of anti-hypertension medications at the last follow-up visit was similar among stent and medical groups for both the low (3.2+/−1.3 s.d. vs 3.3+/−1.4 s.d., respectively, p=0.22) and high uACR cohorts (3.6+/−1.5 s.d. vs. 3.7+/−1.4 s.d., respectively, p=0.6). The use of angiotensin converting enzyme inhibitors or angiotensin receptor blocker medication was similar between the stent and medical treatment groups in both cohorts, and in Cohort 1 82% in the medical group (120/147) and 76% in the stent group (116/153) were taking either medication at close out (p=0.27, Chi-squared). For the entire group with baseline uACR (n=826), the correlation between baseline eGFR and baseline uACR was weak (r=.23).

Figure 3.

Figure 3

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Systolic Blood Pressure Treatment Effects. Systolic blood pressure (group mean ± 1 SE) over time. Difference not significant for Cohort 1 (n=413, p=.58). Test for interaction of group*visit P-value is 0.68. There is a trend favoring stent in Cohort 2 (n=413, p=.052). Test for interaction of group*visit P-value is 0.45. Cohort 1=baseline uACR<=22.5 mg/g; Cohort 2=baseline uACR>22.5 mg/g.

Discussion

This analysis shows that patients in the CORAL study with baseline uACR <22.5 mg/g experienced fewer cardiovascular, renal, and mortality events in the stent group compared to the medical therapy group. This was observed despite there being no difference in systolic blood pressure between treatment groups in Cohort 1, and no difference in ACEI/ARB use.

Although moderately increased albuminuria (uACR >30 <300 mg/g) is present in 8–15% of patients with hypertension13, and is common in those with renal artery stenosis8, the relationship between moderately increased albuminuria and treatment outcomes in patients undergoing renal artery stent placement has not been described. This is potentially an important issue; in the CORAL study population 44% of participants had at least moderately increased baseline albuminuria (uACR 30 mg/g or greater) (Table 1). If patients with moderately or severely increased albuminuria are predestined for a higher rate of cardiovascular events than those without, and that natural history is not modifiable by revascularization of stenotic renal arteries, then inclusion of large numbers of patients with moderate or severe albuminuria would bias studies of renal artery revascularization away from a statistically significant treatment effect and toward the null hypothesis. Similarly, if patients with uACR <22.5 mg/g benefit from stent placement, that is important from a public health standpoint, as its use could improve patient selection and outcomes for roughly half of the patients with renal artery stenosis and appropriate clinical presentations.

There is biologic plausibility of the findings that patients with elevated uACR don’t benefit from revascularization of stenotic renal arteries. Increased uACR can be considered a window on systemic endothelial and overall cardiovascular health14, 15. Elevated uACR has a linear effect on cardiovascular and renal event risk that is independent from GFR7, and uACR >=100 mg/g is associated with double the mortality risk of a uACR of <=5 mg/g7. Increased uACR is associated with microvascular damage including loss of integrity of the endothelial monolayer, systemic arteriolar intimal and medial thickening, increased oxidative stress16, 17, increased endothelial cell apoptosis16, and increased progression of atherosclerosis17, and is also associated with increased carotid artery intimal-medial thickness18 and cardiac hypertrophy19, all of which may explain why increased uACR is associated with increased rates of myocardial infarction, stroke, hospitalization for congestive heart failure, cardiovascular death and overall mortality20–25. Although the uACR cutoff that showed benefit of stenting in this study, 22.5 mg/g, is lower than the usual cutoff for moderate albuminuria (uACR>=30<300 mg/g), the traditional cutoff is arbitrary, and in fact a large meta-analysis reported increased cardiovascular risk with uACR >=10 mg/gm23.

The search for a convenient biomarker that could predict favorable outcomes from renal artery revascularization has been long and has included renal vein renin sampling26, captopril renography27, peripheral renal vein renin28, kidney size29, renal resistive index30, and serum brain natriuretic peptide levels31, but there is no consensus on an ideal biomarker and none were used to select patients for the two largest randomized clinical trials of renal artery stenting, CORAL and ASTRAL3, 4. Some believe that patients with the most refractory blood pressure32, 33, renal fractional flow reserve34, stenosis severity35, or trans-stenotic pressure gradients36 benefit most from renal artery stenting. However, when examined for the CORAL study population there were no significant differences in treatment outcomes based on severity of baseline hypertension, percent stenosis, or trans-lesion pressure gradients37.

Renal artery stenting is currently infrequently performed, probably because of multiple negative randomized clinical trials. Nevertheless, CORAL data suggest that those with low levels of albuminuria may in fact benefit from revascularization of renal artery stenoses, and if confirmed in a subsequent randomized clinical trial, uACR could serve as a widely available and inexpensive biomarker to screen for patients for whom renal artery revascularization may be clinically beneficial, especially for those at highest baseline risk of cardiovascular events.

Limitations

The analyses in this study were not part of the original statistical plan for the CORAL study, and no adjustments were made for multiple comparisons. This raises the possibility that the finding of improved outcomes after stent placement for those in the low uACR stratum could be attributed to sampling variability, and we caution against drawing inferences on the wider population of patients similar to those described in the CORAL study. However, uACR was identified as an important variable using principal component analysis (PCA), which is an accepted statistical technique for detecting dominant patterns in large data sets12, rather than by exhaustive data mining, possibly reducing the chance of type I error. The observation of multiple better cardiovascular and renal outcomes with stenting in patients with low uACR, as well as an improvement in overall survival, also argues against statistical noise. The number of patients in the low uACR stratum was large (n=413) and the p-values for some of the endpoints were small (e.g., <.01), increasing the likelihood that the sample is representative of the underlying population. Conversely, the lack of significant differences in systolic blood pressure between treatment groups raises questions about the mechanism for improved outcomes for those undergoing stent placement in Cohort 1.

Another limitation is that although participants randomized to treatment group, there are some differences in baseline characteristics in both uACR cohorts by treatment group. For example, in Cohort 1 there is more prior heart failure and more global renal ischemia in the stent group (bilateral renal artery stenosis or unilateral stenosis in a uninephric patient), but fewer prior MI’s and smokers. These differences appear within the range of what is typically observed in randomized trials and do not appear to favor one treatment group over the other.

Perspectives

In this post-hoc study of CORAL study data, low baseline uACR was associated with better patient outcomes in the stent group compared with the medical therapy group. Since this finding could be attributable to sampling variability, further research is needed.

Supplementary Material

Supplemental material

Novelty and Significance.

What is new

The CORAL study and other RCT’s have not shown any positive treatment effect of renal artery stenting. However, in this manuscript we report a novel observation—that stents significantly improved outcomes for patients with low baseline urine albumin/creatinine ratios. This finding was confirmed using the primary endpoint in CORAL, multiple components of the primary endpoint, and plus overall survival.

What is relevant

Although done without adjustment for multiple comparisons, there is statistical rigor to these observations. But, we caution against considering these results definitive. They should be examined in another study. If confirmed this information would likely transform management of renal artery stenosis.

Summary

Retrospective review of CORAL study data indicate that patients with atherosclerotic renal artery stenosis and low levels of urine albuminuria might derive substantial benefit from renal artery stent placement.

Acknowledgments

This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Numbers U01HL071556, U01HL072734, U01HL072735, U01HL072736, and U01HL072737. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Drug for this study was provided by AstraZeneca (Wilmington, DE), device support was provided by Cordis Corporation (Bridgewater, NJ) and supplemental financial support was granted by Cordis Corporation and Pfizer Inc. The CORAL Study was registered on ClinicalTrials.gov on April 19, 2004 (identifier NCT00081731).

Sources of Funding: This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Numbers U01HL071556, U01HL072734, U01HL072735, U01HL072736, and U01HL072737. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Drug for this study was provided by AstraZeneca (Wilmington, DE), device support was provided by Cordis Corporation (Bridgewater, NJ) and supplemental financial support was granted by Cordis Corporation and Pfizer Inc. The CORAL Study was registered on ClinicalTrials.gov on April 19, 2004 (identifier NCT00081731).

Abbreviations

CORAL

cardiovascular outcomes with renal atherosclerotic lesions

eGFR

estimated glomerular filtration rate

EMP

endothelial apoptotic microparticles

EPC

endothelial progenitor cells

HDL

high-density lipoprotein

PCA

principal component analysis

uACR

urine albumin/creatinine ratio

VEGF

vascular endothelial growth factor

Footnotes

Clinical Trial Registration: ClinicalTrials.gov on April 19, 2004 (identifier NCT00081731), https://clinicaltrials.gov/ct2/show/NCT00081731?term=NCT00081731&rank=1

Conflict of Interest Disclosures: Timothy P, Murphy: Current Employer: Rhode Island Medical Imaging, Inc.; Ownership Interest: Sentient Bioscience, Summa Therapeutics, Saphena Medical, Anaxiom, Inc.; Research Funding: Cordis/Johnson & Johnson; Abbott Vascular; National Institutes of Health; Novate Medical; The Medicines Company; National Heart Lung and Blood Institute; Honoraria: Merit Medical. Christopher J. Cooper: Current Employer: University of Toledo; Research Funding: Pfizer, AstraZeneca, Cordis, National Heart Lung and Blood Institute. Karol M. Pencina: Disclosure Information: nothing to disclose. Ralph B. D’Agostino: Current Employer: Boston University; Consultancy Agreements: Harvard Clinical Research Institute (consultant), Progeria Foundation (consultant); Scientific Advisor or Membership: Statistics in Medicine (editor), New England Journal of Medicine (editorial board). Joseph Massaro: Current Employer: Boston University School of Public Health, Harvard Clinical Research Institute; Disclosure Information: nothing to disclose. Donald Cutlip: Current Employer: Beth Israel Deaconess Medical Center; Research Funding: Medtronic. Kenneth A. Jamerson: Current Employer: University of Michigan Health System; Research Funding: National Institutes of Health; Scientific Advisor or Membership: National Institutes of Health. Alan Matsumoto: Current Employer: University of Virginia; Ownership Interest: Volcano; Research Funding: W.L. Gore, Medtronic, Insightec, Cook; Honoraria: Trivascular, Bolton Medical, W.L. Gore; Scientific Advisor or Membership: Boston Scientific, Tenex Medical, BrightWater. William L. Henrich: Current Employer: University of Texas-San Antonio; Disclosure Information: nothing to disclose. Joseph I. Shapiro: Current Employer: Marshall University; Ownership Interest: ADS Biotechnology. Honoraria: West Virginia University; University of Colorado; Ohio State University; Cleveland Clinic Foundation; Wayne State University; Henry Ford Hospital; Medical University of South Carolina; University of Toledo; University of Pisa; University of Catania. Scientific Advisor or Membership: ADS Biotechnology Board of Directors (Chairman); Alliance for Paired Donation Board of Directors; American Heart Association (Ohio Valley Affiliate) Board of Directors; Promedica Health Systems Academic Health Center Board of Directors; Regional Growth Partnership of NW Ohio Scientific Advisory Board; Editorial Board Member for Kidney Int, Frontiers Biosci. Biol Res Nurs, Am J Medicine, Am. Soc. Art Intern Org, Hypertension, Int J Hypertens, J Signal Trans, World J Hypertens. Katherine R. Tuttle: Current Employer: Providence Health Care, University of Washington School of Medicine; Consultancy Agreements: Eli Lilly, Amgen, Noxxon Pharma; Honoraria: Primary Care Update, American Diabetes Association, National Kidney Foundation, Spokane Society of Internal Medicine, University of Colorado, Quintiles, Duke University, University of North Carolina, Cleveland Clinic; Scientific Advisor or Membership: CJASN, Am J Nephrol, NIDDK/NKDEP, Kidney Health Initiative, US Veteran’s Administration. David J. Cohen: Current Employer: St. Luke’s Hospital-Kansas City; Disclosure Information: Research Funding: Medtronic, Boston Scientific, Abbott Vascular; Consultancy Agreements: Medtronic, Abbott Vascular; Michael Steffes: Current Employer: University of Minnesota; Disclosure Information: nothing to disclose. Qi Gao: Current Employer: Harvard Clinical Research Institute; Disclosure Information: nothing to disclose. Christopher Metzger: Current Employer: Wellmont-Holston Valley Medical Center; Consultancy Agreements: Abbott, TriVascular; Honoraria: Abbott, Boston Scientific, Bard. William Abernethy: Current Employer: Asheville Cardiology Associates; Disclosure Information: nothing to disclose. Stephen C. Textor: Current Employer: Mayo Clinic; Research Funding: Stealth Peptides, Inc. John Briguglio: Current Employer: Lancaster General Hospital; Disclosure Information: nothing to disclose. Alan Hirsch: Current Employer: University of Minnesota; Consultancy Agreements: Merck, Novartis, Bayer; Research Funding: AstraZeneca, National Heart Lung and Blood Institute, Pluristem; Other Interest/Relationships: Tactile Medical: Chief Medical Officer. Sheldon W. Tobe: Consultancy Agreements: AbbVie Inc.; Research Funding: Astra Zeneca, Pfizer, Bayer; Scientific Advisor or Membership: American Society of Hypertension. Lance D. Dworkin: Current Employer: University Medicine Foundation; Research Funding: Astra Zeneca, National Institutes of Health, Cordis/Johnson & Johnson; Scientific Advisor or Membership: Clinical Journal of the American Society of Nephrology editorial board.

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Supplemental material
NIHMS810866-supplement-Supplemental_material.pdf (659.9KB, pdf)

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