Ultra-Low-Dose Contrast Using Transluminal Renal Angioplasty: The ULTRA Study

Background Although severe atherosclerotic renal artery stenosis (ARAS) is a predictor of future cardiovascular events, large trials have not shown the benefits of percutaneous transluminal renal angioplasty (PTRA). This study aimed to validate the safety and efficacy of PTRA using low-concentration digital subtraction angiography (LC-DSA) in patients with severe ARAS and advanced chronic kidney disease (CKD). Materials and Methods This prospective study was conducted between August 2018 and October 2021. Eighteen patients with 20 lesions, CKD stage 3b or worse, and significant renal artery stenosis were included and underwent PTRA using ultra-low-dose contrast medium. The primary endpoint was a change in renal function based on serum creatinine (sCr) level. Results The mean sCr level significantly improved from 3.34 ± 1.8 mg/dL pre-PTRA to 2.48 ± 1.19 mg/dL at 1 month post-PTRA (P = .02). The mean amount of contrast used was 8.3 ± 3.9 mL per vessel. More severe stenosis and rapid deterioration of renal function before treatment were associated with improved kidney function. No cardiovascular or renal complications such as stroke or contrast-induced nephropathy were observed during the 30-day period. Conclusions PTRA using an ultra-low-dose contrast medium is safe and provides acceptable results.


Introduction
Severe atherosclerotic renal artery stenosis (ARAS) is a cause of dialysis 1 and a predictor of future cardiovascular events. 2 Although small trials have indicated that percutaneous transluminal renal artery angioplasty (PTRA) improves renal function, [3][4][5][6][7] randomized controlled trials (RCTs) have shown no difference in renal function or cardiovascular events between patients treated with guideline-directed medical therapy (GDMT) alone and those treated with PTRA and GDMT. [8][9][10] However, unlike previous studies, a recent report demonstrated that PTRA reduced cardiovascular events in a group with improved renal function. 11 Therefore, it is important to identify those patients who can benefit from PTRA and provide them with treatment opportunities.
One of the reasons why PTRA has failed to show effectiveness for renal function in RCTs is the use of a large amount of contrast media (up to approximately 125 mL), 12 and PTRA may be useful for selecting patients according to lesion severity and chronic kidney disease (CKD) degree. Endovascular therapy using diluted contrast has been suggested to prevent contrast-induced nephropathy (CIN) 13 ; however, the safety and efficacy of PTRA using reduced volumes of diluted contrast are unknown.
This study aimed to validate the safety and efficacy of PTRA by using low-concentration digital subtraction angiography (LC-DSA) in patients with severe ARAS and advanced CKD.

Study Design and Population
This single-center prospective observational study was approved by the ethics committee of our institution and registered with the University Hospital Medical Information Network-Clinical Trial Registry as recommended by the International Committee of Medical Journal Editors (no. UMIN000034174).
This study included consecutive patients who underwent PTRA using an ultra-low-dose contrast medium at our institution between August 2018 and October 2021. The eligibility criteria were 1 : CKD stage 3b or worse; and 2 significant renal artery stenosis, defined as at least 80% on computed tomography or magnetic resonance imaging or as a peak systolic velocity ≥300 cm/s on renal duplex ultrasonography. The exclusion criteria were renal atrophy defined as a kidney <7 cm, renal artery stenosis due to fibromuscular dysplasia, previous initiation of dialysis, or PTRA during endovascular aneurysm repair.

Procedure
The patients were administered dual antiplatelet therapy with aspirin and thienopyridine before the procedure. A 4.5-French guiding sheath was inserted into the radial or femoral artery and advanced to the renal artery using the non-touch technique. LC-DSA was performed to detect renal artery stenosis ( Figure 1A and 1B). In some cases, a hydro-coated wire was used to cross the lesion. Predilatation was performed, and a balloon-expandable bare metal stent was deployed at the ostial lesion slightly protruding into the aorta in all patients ( Figure 1C). We chose a stent size that matched to the native vasculature. A complete angiogram was also performed to assess the entire kidney ( Figure 1D). Finally, we evaluated LC-DSA quality. The patients were followed by duplex at 6 months and 12 months after the procedures.
The primary endpoint was a change in sCr level assessed by comparing measurements before and 1 month after PTRA. The secondary endpoints were the dose of the contrast medium, procedural complications, renal events, and major adverse cardiovascular events.
Angiography was performed using an Alphenix INFX-8000H (Canon Medical Systems, Tustin, CA, USA). To enable the capture of high-quality angiographic images, the DSA parameters were adjusted to improve image sensitivity and contrast and reduce edge intensity.
The contrast agent used in the procedure was diluted to a solution containing 1 mL of iopamidol 755 mg/mL contrast medium and 9 mL saline. The contrast medium was that used for the standard PTRA. In all cases, saline was administered at 1 mL/kg for 12 hours prior to the procedure.

Definition
Procedural complications included vessel rupture, bleeding requiring blood transfusion, and cholesterol crystal embolization. Renal events were defined as CIN, dependence on hemodialysis, and renal transplantation. Major adverse cardiovascular events were defined as death, myocardial infarction, hospitalization for congestive heart failure, or stroke. CKD was defined and classified by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative in 2002. Procedural success was defined as residual steno-sis<30% without a flow delay. CIN was defined as an elevation in serum creatinine (sCr) of more than 25% or ≥.5 mg/dL (44 μmol/L) from baseline within 48 h. LC-DSA quality was evaluated at the following three levels: Good, equivalent to normal contrast angiography and quantitative vascular analysis (QVA) is possible; Fair, evaluable but QVA not possible; and Bad, not evaluable.

Statistical Analysis
All statistical analyses were performed using SPSS software (SPSS Inc, Chicago, Illinois, USA). Continuous variables are reported as mean ± standard deviation (SD), whereas categorical variables are presented as number and percentage. Continuous variables were examined using the paired t-test or Mann-Whitney U test. P values <.05 were considered statistically significant.

Patient Characteristics
Twenty lesions were treated in 18 patients. Three patients were excluded because they underwent PTRA during endovascular aortic repair for an abdominal aortic aneurysm and aortic dissection. Overall, 17 lesions from 15 patients (16 procedures) were examined. The baseline patient characteristics are shown in Table 1.
All patients had hypertension. The patients were on an average of 2.8 antihypertensive agents (ie, diuretic, calciumchannel blocker, beta-blocker, renin angiotensin system [RAS] blocker, and alpha-blocker); nine (60.0%) were taking RAS blockers at baseline. The mean stenosis of the renal artery was 92% by visual estimation, and three cases demonstrated total occlusion of the involved artery.

Procedural Results
Procedural success was achieved in all cases. Procedural data are shown in Table 2. The mean amount of contrast used was 8.3 ± 3.9 mL per procedure and 7.8 ± 3.9 mL per vessel. There were no cases of "bad" LCA-DSA quality, and 70.1% of cases had "good" LCA-DSA quality. Data are presented as n (%) or mean ± standard deviation. BMI, body mass index; GFR, glomerular filtration rate; RAS, renin-angiotensin system. a N = 14. Urinary protein levels were not measured in one patient. None of the patients required distal protection devices, while one required intravascular ultrasound (IVUS). Figure 2 shows the mean sCr levels before (3.34 ± 1.8 mg/dL) and after (2.48 ± 1.19 mg/dL) treatment (P = .02). Renal function showed significant improvement after one month of treatment, and improvement in renal function was maintained over a 12-month period (3 months: 2.45 ± 1.72; 6 months: 2.48 ± 1.21; 12 months: 2.54 ± 1.57). The number of antihypertensive agents decreased to 2.4 ± 1.2 after one month after PTRA. It was not statistically significant (P = .055). After one month, a ≥20% decrease in sCr was documented in eight patients, whereas the sCr level remained unchanged (within ±20% of the pretreatment value) in seven patients. None of the patients demonstrated a ≥20% increase in sCr levels vs the pretreatment values.

Primary and Secondary Outcomes
The patients were analyzed based on whether they responded to the intervention. The responder group included patients who demonstrated an improvement of at least 20% in sCr levels, whereas the non-responder group showed changes within 20% of the corresponding pre-treatment values. Table 3 compares the patient and procedural characteristics between the two groups. Figure 3 shows the time course of the sCr levels between the two groups. The responder group tended to have the most recent renal function worsening. In the responder group, the average extent of renal artery stenosis was 91.4 ± 7.8%, whereas most of the patients in the non-responder group had <90% stenosis. Renal function tended to worsen in the responder group. Age, sex, history of other atherosclerotic diseases (coronary artery disease, peripheral artery disease, and cardiovascular disease), or proteinuria >1.0 g/g・Cr did not contribute to the primary outcome. Patients with progressively reduced renal function and severe renal artery stenosis are more likely to benefit from PTRA.
No cardiovascular events or complications were noted during the 30 day study period. After 30 days, renal function deteriorated in three cases. One patient temporarily required hemodialysis but stopped three weeks after PTRA, while another patient was introduced to dialysis 14 months after catheterization. The patients' renal functions gradually deteriorated. The last was introduced to dialysis two months after the procedure because of cholesterol crystal embolization (CCE). Target lesion revascularization was performed on postoperative day 175 in one case. Two deaths occurred after an average followup of 594 days.

Discussion
We used LC-DSA in 20 PTRA cases and found significantly improved renal function. To the best of our knowledge, this is the first report of PTRA using LC-DSA. Our method dramatically reduced the use of contrast media using a technique similar to that of a standard catheter. All treatments were performed with an extremely small amount of contrast, and QVA was possible in 71% of cases. Previous RCTs failed to show the superiority of PTRA over GDMT because PTRA was associated with distal embolization, CCE, and CIN. Some studies have demonstrated the benefits of using distal protection systems to improve renal function. 12,14 However, distal protection systems are difficult to use during PTRA because of their short landing zones; thus, they are not generally applied in endovascular procedures, with the exception of carotid artery stenting.
CIN is an important complication of catheter interventions. The most effective way to prevent CIN is to reduce the contrast medium volume; however, it is difficult to do so in normal angiography. 12,15,16 The average volume of iodinated contrast medium used in previous studies was approximately 100 mL. Some studies proposed that carbon dioxide (CO 2 ) can be a safe and effective contrast medium 17 ; however, it is often difficult to evaluate the abdominal area due to abdominal gas. Moreover, a recent CO 2 angiography registry reported a high mortality rate of 2% (2/100). 18 Thus, the routine use of CO 2 is currently not recommended because of its risks and poor imaging quality.
Hayakawa et al demonstrated the efficacy of diluted contrast for lower-extremity endovascular therapy. 13 Using LC-DSA, they were able to dramatically reduce the amount of contrast required without using IVUS. Although the use of IVUS can reduce the contrast requirement in some cases, it is  only useful for precise stent positioning. Moreover, IVUS cannot evaluate the renal artery ostium or determine whether angiography has been completed; thus, its use in PTRA is limited. A major limitation of LC-DSA is motion artifacts, as abdominal gas often interrupts clear renal artery imaging. Abdominal gas should be managed in cases in which LC-DSA is used. Among patients with ARAS and CKD, the benefits of renal artery revascularization may be limited if renal dysfunction is due to other causes such as CCE or renal parenchymal disease. Almost all of the patients in this study were referred to our institution by nephrologists, meaning that each was evaluated properly and judged as most likely to benefit from revascularization procedures. Simple stenosis screening may be inadequate when considering the need for renal revascularization.
Lesion selection is also an important factor in achieving good results. The Angioplasty and Stent for Renal Artery Lesions (ASTRAL) trial treated a large number of patients with moderate stenosis. Stenosis measurements were performed at different sites instead of a single laboratory. 9 However, in the ASTRAL trial, 41% of patients had less than 70% stenosis. In contrast, this study showed that patients with more severe stenosis, such as those close to obstruction, were more likely to benefit from revascularization. The ASTRAL trial also highlighted the impact of renal function on the overall procedural success. The mean estimated glomerular filtration rate in the ASTRAL and Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trials was 39.8-58 mL/min/1.73 m 2 . Compared with these trials, the renal function of our patients was significantly worse at 21.6 mL/min/ 1.73 m 2 . The difference in results between these large RCTs and our study may be due to differences in the degree of stenosis and renal function in the study populations. In particular, we treated patients with severe stenosis and worse renal function who required revascularization.
Previous studies have suggested that PTRA may be more effective in patients with low albuminuria [19][20][21] or a rapidly declining renal function. [21][22][23] This study demonstrated that proteinuria did not contribute to the primary outcome. However, patients who presented with a rapidly declining renal function were more likely to benefit from PTRA.
This study had some limitations. First, it was a singlecenter prospective study that examined a small sample of patients. Thus, our results require validation in a multicenter prospective study with a larger sample population. Second, motion artifacts may significantly decrease the image quality provided by LC-DSA. Subtraction divergence resulted in high degrees of image noise, which made it difficult to manage abdominal gas. Third, none of the patients in this study were treated with IVUS or a distal protection system. Finally, we did not examine patients with fibromuscular dysplasia.

Conclusion
PTRA with ultra-low-dose diluted contrast medium is safe and effective in patients with severe ARAS.