Ultra-Low dose contrast using Transluminal Renal Angioplasty (ULTRA study)

Background Severe atherosclerotic renal artery stenosis (ARAS) is a predictor of future cardiovascular events and should be managed effectively. This study aimed to validate the safety and e�cacy of percutaneous transluminal renal angioplasty (PTRA) using low concentration digital subtraction angiography (LC-DSA) among patients with severe ARAS and advanced chronic kidney disease (CKD). Methods This prospective study conducted between August 2018 and August 2020. Patients with CKD stage 3b or worse and signi�cant renal artery stenosis were included in this study and underwent PTRA with ultra-low dose contrast medium. The primary endpoint was a change in renal function, based on serum creatinine (sCr) levels.


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

Study design and population
This study followed a single center, prospective, observational design.The study was approved by the ethics committee of our institution and registered with the University Hospital Medical Information Network-Clinical Trial Registry (UMIN-CTR), as recommended by the International Committee of Medical Journal Editors (no.UMIN000034174).
This study included consecutive patients who underwent PTRA with ultra-low dose contrast medium in our institution between August 2018 and August 2020.The eligibility criteria were (1) CKD stage 3b or worse and (2) signi cant renal artery stenosis, de ned as stenosis of at least 80% on computed tomography or magnetic resonance imaging or as peak systolic velocity ≥300 cm/sec on renal duplex ultrasonography.The exclusion criteria included renal atrophy de ned as < 7cm kidney size, renal artery stenosis due to bromuscular dysplasia, previous initiation of dialysis, cholesterol crystal embolization, or PTRA during endovascular aneurysm repair.

Procedure
The patients were placed on dual antiplatelet therapy with aspirin and thienopyridine before the procedure.A 4.5 French guiding sheath was inserted in a radial or femoral artery and advanced to the renal artery with the non-touch technique.LC-DSA was performed to detect renal artery stenosis (Figure 1A, B).In some cases, a hydro-coated wire was used to cross the lesion.Pre-dilatation was performed, and a stent was deployed in all cases with ostial lesions (Figure 1C).A complete angiogram to assess the entire kidney was also performed (Figure 1D).The primary endpoint was a change in sCr levels, which was assessed by comparing measurements one month before and after PTRA.The secondary endpoints were dose of contrast medium, procedure complications, renal events, and major adverse cardiovascular events.Angiography was performed using the Alphenix INFX-8000H (Canon Medical Systems, Tustin, California, USA).To obtain high quality angiographic images, DSA parameters were adjusted to improve image sensitivity and contrast and reduce edge intensity.
The contrast used in the procedure was diluted in a solution containing 1 mL of Iopamidol 755 mg / mL contrast medium and 9 mL of saline.The contrast medium was the same as that used in standard PTRA.In all cases, saline was administered at 1mL/kg for 12 hours prior to the procedure.

De nition
Procedure complications were de ned as vessel rupture, any bleeding requiring blood transfusion, and cholesterol crystal embolization.Renal events were de ned as CIN, dependence on hemodialysis, and renal transplantation.Major adverse cardiovascular events were de ned as death, myocardial infarction, hospitalization for congestive heart failure, and stroke.The de nition and classi cation of CKD were introduced by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative in 2002.
Procedure success was de ned as residual stenosis <30% without ow delay.CIN was de ned as an elevation of serum creatinine (sCr) of more than 25% or ≥0.5 mg/dL (44 µmol/L) from baseline within 48 h.

Statistical Analysis
All statistical analyses were performed using SPSS (SPSS Inc., Chicago, Illinois, USA).Continuous variables are reported as mean ± standard deviation (SD), whereas categorical variables were presented as numbers with percentages.Continuous variables were examined using the paired t-test or Mann-Whitney U test.A P value <0.05 was considered statistically signi cant.

Patient characteristics
Fifteen lesions were treated in thirteen patients.Two cases were excluded because they underwent PTRA during endovascular aortic repair for an abdominal aortic aneurysm and aortic dissection, respectively.Overall, 13 lesions of 11 patients, and 12 procedures were examined.The baseline characteristics of our patients are presented in Table 1.
All patients had hypertension and dyslipidemia.The patients were on an average of 2.5 antihypertensive agents (i.e., diuretic, calcium-channel blocker, beta-blocker, renin angiotensin system [RAS] blocker, and alpha-blocker); seven (63.6%) patients were taking RAS blockers at baseline.The mean lesion stenosis was 91%, and two cases demonstrated total occlusion of the involved artery.

Procedure results
The procedural data are shown in Table 2.The mean amount of used contrast was 9.5 ± 3.5 mL per procedure and 8.8 ± 4.0 mL per vessel.None of the cases required an intravascular ultrasound (IVUS) or distal protection devices.

Primary and secondary outcomes
Figure 2 shows the mean sCr levels before (3.18 ± 1.8 mg/dL) and one month (2.34 ± 1.17 mg/dL) after treatment (p =0.039).A ≥20% decrease in sCr was documented in ve patients, whereas the sCr level remained unchanged (within ±20% of the pre-treatment value) in six patients.None of the patients demonstrated a ≥20% increase in sCr levels compared to pre-treatment values.
The cases were analyzed depending on whether they responded to the intervention.The responder group was comprised of patients who demonstrated an improvement of at least 20% in sCr levels, whereas the non-responder group showed changes within 20% of the corresponding pretreatment values.Table 3 compares the patients and procedure characteristics between these two groups.Figure 3 shows the time course of sCr levels in these two groups.The responder group tended to have the most recent worsening of renal function.In the responder group, the average extent of renal artery stenosis was 99.4% (range, 99-100%), whereas most of the patients in the non-responder group had less than 90% stenosis.Renal function tended to be worse in the responder group.Age, gender, history of other atherosclerotic disease (coronary artery disease, peripheral artery disease, cardiovascular disease), or proteinuria >1.0 g/g Cr did not contribute to the primary outcome.Patients with progressively reduced renal function and renal artery stenosis of at least 99% were more likely to bene t from PTRA.
No cardiovascular events and complications were noted during our study.While renal function deteriorated slightly in some cases, none of them met the de nition of CIN.One patient was temporarily started on hemodialysis but stopped three weeks after PTRA.

Discussion
This prospective study demonstrated that PTRA with ultra-low volume contrast was safe and improved renal function.
Previous RCTs failed to show the superiority of PTRA to GDMT, because PTRA has been associated with distal embolization, cholesterol embolization and CIN.Some studies demonstrated the bene t of using distal protection systems to improve renal functions (12,14).However, distal protection systems are di cult to use during PTRA, because of a short landing zone.These are not generally applied to endovascular procedures with the exception of carotid artery stenting.
CIN is a major complication of catheter interventions.The most effective method to prevent CIN is to reduce the amount of contrast medium; however, it is di cult to reduce the amount of contrast medium in normal angiography (12,15,16); the average volume of iodinated contrast medium used in the previous studies was approximately 100 mL.Some studies have proposed that carbon dioxide (CO 2 ) can be used as a safe and effective contrast medium, however, the recent CO 2 angiography registry reported a mortality rate of 2% (2/100) (18).The routine use of CO 2 is currently not recommended.
Hayakawa et al. demonstrated the e cacy of using diluted contrast for endovascular therapy of the lower extremity (13).By using LC-DSA, they were able to dramatically reduce the amount of required contrast without using IVUS.While an IVUS can reduce the contrast requirement in some cases, it only useful for precise stent positioning.Moreover, an IVUS cannot evaluate the renal artery ostium or determine whether the angiography has been completed; its use in PTRA is limited.A major limitation of LC-DSA is motion artifact; abdominal gas oftentimes interrupts the clear renal artery imaging.Abdominal gas should be managed in cases where LC-DSA will be used.
Among patients with ARAS and CKD, the bene ts of renal artery revascularization may be limited if the renal dysfunction was due to other causes, such as cholesterol crystal embolization or renal parenchymal disease.In this study, almost all patients were referred to our institution by nephrologists, which meant that patients were evaluated properly and assessed to most likely bene t from revascularization procedures.Simple stenosis screening may be inadequate when considering the need for renal revascularization.
Lesion selection is also an important factor for obtaining good results.The Angioplasty and Stent for Renal Artery Lesions (ASTRAL) trial examined a large number of cases with moderate stenosis.Stenosis measurements were performed in different sites instead of a single laboratory, (9) and stenosis rates of 70-80% or more were considered signi cant to require revascularization (24).However, the ASTRAL trial demonstrated that stenting moderate lesions may not signi cantly improve renal function.Moreover, the study showed that patients with more severe stenosis, such as those close to obstruction, were more likely to bene t from revascularization.The ASTRAL trial also highlighted the impact of renal function on overall procedural success.The mean estimated glomerular ltration rate in the ASTRAL and Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trials ranged from 39.8-58 mL/min/1.73m 2 .Compared to these trials, the renal functions of our patients were signi cantly worse at 23.5 mL/min/1.73m 2 .The difference in the results between the studies may be due to differences in the degree of stenosis and renal function in the study populations.
Previous studies suggested that PTRA may be more effective in patients with low albuminuria (19,20,21) or who present with a rapid decline in renal function (21,22,23).This study demonstrated that proteinuria did not contribute to the primary outcome; however, patients who presented with a rapid decline in renal function were more likely to bene t from PTRA.This study has some limitations.First, this was a single-center prospective study that examined a small sample of patients.The results have to be validated by a multi-center prospective study that examines a larger sample population.Second, motion artifacts may have signi cantly decreased the image quality provided by LC-DSA.Subtraction divergence resulted in high degrees of image noise that made it di cult to manage abdominal gas.Third, none of the patients in this study used IVUS or distal protection systems.Lastly, we did not examine patients with bromuscular dysplasia.
In conclusion, PTRA with ultra-low dose diluted contrast medium was safe and improved renal function in some cases.

Figures
Figures

Figure 1 Representative
Figure 1

Figure 3 Comparison
Figure 3 Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.