Wencan He

Use of Renin-Angiotensin Inhibitors in People with Renal Artery Stenosis

BACKGROUND AND OBJECTIVES People with atherosclerotic renal artery stenosis may benefit from renin-angiotensin inhibitors, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers, but little is known about the factors associated with their use. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Cardiovascular Outcomes in Renal Atherosclerotic Lesions study (ClinicalTrials.gov identified: NCT00081731) is a prospective, international, multicenter clinical trial that randomly assigned participants with atherosclerotic renal artery stenosis who received optimal medical therapy to stenting versus no stenting from May 2005 through January 2010. At baseline, medication information was available from 853 of 931 randomly assigned participants. Kidney function was measured by serum creatinine-based eGFR at a core laboratory. RESULTS Before randomization, renin-angiotensin inhibitors were used in 419 (49%) of the 853 participants. Renin-angiotensin inhibitor use was lower in those with CKD (eGFR<60 ml/min per 1.73 m(2)) (58% versus 68%; P=0.004) and higher in individuals with diabetes (41% versus 27%; P<0.001). Presence of bilateral renal artery stenosis or congestive heart failure was not associated with renin-angiotensin inhibitor use. Although therapy with renin-angiotensin inhibitors varied by study site, differences in rates of use were not related to the characteristics of the site participants. Participants receiving a renin-angiotensin inhibitor had lower systolic BP (mean ± SD, 148 ± 23 versus 152 ± 23 mmHg; P=0.003) and more often had BP at goal (30% versus 22%; P=0.01). CONCLUSIONS Kidney function and diabetes were associated with renin-angiotensin inhibitor use. However, these or other clinical characteristics did not explain variability among study sites. Patients with renal artery stenosis who received renin-angiotensin inhibitor treatment had lower BP and were more likely to be at treatment goal.

Effect of CD40 and sCD40L on renal function and survival in patients with renal artery stenosis

Activation of the CD40 receptor on the proximal tubular epithelium of the kidney results in fibrosis and inflammation in experimental models of kidney injury. Soluble CD40 ligand is released by activated platelets. The role of CD40-soluble CD40 ligand in patients with ischemic renal disease is unknown. Plasma levels of CD40 and soluble CD40 ligand were measured by enzyme-linked immunosorbent assay in a single center cohort of 60 patients with renal artery stenosis recruited from Salford Royal Hospital, Manchester, United Kingdom. A natural log transformation of CD40 and soluble CD40 ligand was performed to normalize the data. Estimated glomerular filtration rate was used as the primary indicator of renal function. By univariate analysis, low baseline levels of circulating CD40 (R2=0.06; P<0.05) and baseline creatinine (R2=0.08; P=0.022) were associated with loss of kidney function at 1-year follow-up, whereas soluble CD40 ligand was not (R2=0.02; P=ns). In a multiple linear regression model, CD40 (P<0.02) and baseline creatinine (P<0.01) continued to be significantly associated with a decline in renal function (model R2=0.17; P<0.005). Baseline CD40 levels were somewhat lower in patients who died during follow-up (survivors, 7.3±0.9 pg/mL, n=48 versus nonsurvivors, 6.7±1.0 pg/mL, n=12; P=0.06). The CD40/soluble CD40 ligand signaling cascade may be a novel mechanism contributing to the development and progression of renal injury in patients with atherosclerotic renal artery stenosis.

Regional and physician specialty–associated variations in the medical management of atherosclerotic renal–artery stenosis

For people enrolled in Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL), we sought to examine whether variation exists in the baseline medical therapy of different geographic regions and if any variations in prescribing patterns were associated with physician specialty. Patients were grouped by location within the United States (US) and outside the US (OUS), which includes Canada, South America, Europe, South Africa, New Zealand, and Australia. When comparing US to OUS, participants in the US took fewer anti-hypertensive medications (1.9 ± 1.5 vs. 2.4 ± 1.4; P < .001) and were less likely to be treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (46% vs. 62%; P < .001), calcium channel antagonist (37% vs. 58%; P < .001), and statin (64% vs. 75%; P < .05). In CORAL, the identification of variations in baseline medical therapy suggests that substantial opportunities exist to improve the medical management of patients with atherosclerotic renal-artery stenosis.

Cigarette smoking and cardio-renal events in patients with atherosclerotic renal artery stenosis

Cigarette smoking causes cardiovascular disease and is associated with poor kidney function in individuals with diabetes mellitus and primary kidney diseases. However, the association of smoking on patients with atherosclerotic renal artery stenosis has not been studied. The current study utilized data from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL, NCT00081731) clinical trial to evaluate the effects of smoking on the risk of cardio-renal events and kidney function in this population. Baseline data showed that smokers (n = 277 out of 931) were significantly younger at enrollment than non-smokers (63.3±9.1 years vs 72.4±7.8 years; p<0.001). In addition, patients who smoke were also more likely to have bilateral renal artery stenoses and peripheral vascular disease (PVD). Longitudinal analysis showed that smokers experienced composite endpoint events (defined as first occurrence of: stroke; cardiovascular or renal death; myocardial infarction; hospitalization for congestive heart failure; permanent renal replacement; and progressive renal insufficiency defined as 30% reduction of GFR from baseline sustained for ≥ 60 days) at a substantially younger age compared to non-smokers (67.1±9.0 versus 76.1±7.9, p<0.001). Using linear regression and generalized linear modeling analysis controlled by age, sex, and ethnicity, smokers had significantly higher cystatin C levels (1.3±0.7 vs 1.2±0.9, p<0.01) whereas creatinine and estimated glomerular filtration rate (eGFR) were not different from non-smokers. From these data we conclude that smoking has a significant association with deleterious cardio-renal outcomes in patients with renovascular hypertension.

4A.02: STENTING OF ATHEROSCLEROTIC RENAL ARTERY STENOSIS DOES NOT IMPROVE CLINICAL OUTCOMES IN PATIENTS PRESENTING WITH CONGESTIVE HEART FAILURE, AN ANALYSIS OF THE CORAL TRIAL.

Objective: In some guidelines congestive heart failure is an indication for renal artery stenting. We sought to determine, in patients enrolled with a history of congestive heart failure (CHF), the effect of renal artery stenting on clinical outcomes in the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial. Design and method: The CORAL trial is a prospective, international, multicenter clinical trial that randomized participants with atherosclerotic renal artery stenosis, who received optimal medical therapy, to stenting versus no stenting. Optimal medical therapy included treating blood pressure and diabetes to goal, use of an angiotensin receptor-blocking drug, a statin, and anti-platelet therapy. Clinical data from patients with a history of CHF were analyzed using SAS and R software. Glomerular filtration (eGFR) was estimated using the serum creatinine-cystatin-C-CKD-EPI equation. Patients were followed for a median of 43 months (IQR, 31 to 55). Blood pressure was measured in triplicate, after 5 minutes seated quietly, with an oscillometric device. Results: A history of CHF was present at enrollment in 123 of 931 subjects, 69 in the medical therapy group and 54 in the medical therapy + stenting group. Neither the composite event rate (41% vs. 48%, p = 0.51), rate of CHF admission (20% vs. 26%. p = 0.112) nor the rate of cardiovascular death (16% vs. 17%, p > 0.99) differed between medical therapy only and the stent + medical therapy groups. At 2-years follow-up no differences were observed between medical therapy and medical therapy + stent for systolic blood pressure (SBP) (136 ± 26 vs. 136 ± 18 mmHg, p = 0.94) or eGFR (56 ± 23 vs. 56 ± 23 ml/min, p = 0.96). In the longitudinal analysis of eGFR and SBP, neither stent treatment (p = 0.212 and p = 0.9801, respectively) nor the interaction between stent treatment and time (p = 0.429 and p = 0.551, respectively) were significant. Conclusions: Renal artery stenting and optimal medical therapy, when compared to optimal medical therapy only, did not reduce the risk of fatal and nonfatal cardio-renal events in patients that were enrolled with history of congestive heart failure in the CORAL trial. Furthermore, stent treatment of CHF patients did not affect kidney disease progression or blood pressure control.

[OP.2B.01] CIGARETTE USE ALTERS ASSESSMENT OF GLOMERULAR FILTRATION RATE.

Objective: Accurate assessment of glomerular filtration rate (GFR) is important in ascertaining health status, especially in older individuals and in populations at risk of chronic kidney disease. Recently we observed that smokers with renal artery stenosis and renovascular hypertension had lower GFR when estimated by cystatin-C, than with creatinine-based estimates. We sought to resolve this issue. Design and method: Data from the Diabetes Control and Complications Trial (DCCT) were used to estimate GFR in individuals with diabetes. Iohexol clearance was used as the standard, and was compared to GFR estimates using creatinine and cystatin-C. Creatinine and cystatin-C estimates were calculated with the 24-hour urine creatinine clearance and the CKD-EPI cystatin-C. formula, and compared to iohexol based estimates using the Bland-Altman method. Results: There were 441 patients with iohexol, creatinine and cystatin-C values. The average age was 27.6 ± 6.6 years. The mean iohexol GFR for the population was 127.5 ± 19.2 ml/min. The cystatin-C and creatinine-based estimates were close to the iohexol estimates in non-smokers (differing by −7.7 ± 24.7 and −2.7 ± 31.1 ml/min respectively, p = ns). However in smokers, the cystatin-C estimates were considerably lower than iohexol-based GFR estimates (difference = −21.4 ± 25.1 ml/min p < 0.001), while creatinine based estimates were not (difference = −4.6 ± 21.6 ml/min, p = 0.58). Conclusions: Cystatin-C based estimates of GFR are accurate in non-smoking diabetics and yet substantially and significantly underestimate GFR in diabetics that smoke cigarettes.