Toru Misawa,Tomoyo Sugiyama,Yoshihisa Kanaji,Masahiro Hoshino,Masao Yamaguchi,Masahiro Hada,Tatsuhiro Nagamine,Kai Nogami,Yumi Yasui,Eisuke Usui,Tetsumin Lee,Taishi Yonetsu,Tetsuo Sasano,Tsunekazu Kakuta

Toru Misawa,Tomoyo Sugiyama,Yoshihisa Kanaji,Masahiro Hoshino,Masao Yamaguchi,Masahiro Hada,Tatsuhiro Nagamine,Kai Nogami,Yumi Yasui,Eisuke Usui,Tetsumin Lee,Tsunekazu Kakuta,Department of Cardiovascular Medicine,Tsuchiura Kyodo General Hospital,Ibaraki 300-0028,Japan

Taishi Yonetsu,Department of Interventional Cardiology,Tokyo Medical and Dental University,Tokyo 113-8519,Japan

Tetsuo Sasano,Department of Cardiovascular Medicine,Tokyo Medical and Dental University,Tokyo 113-8519,Japan

Abstract BACKGROUND Low-molecular-weight dextran (LMWD) is considered a safe alternative to contrast media for blood displacement during optical coherence tomography(OCT) imaging.AIM To investigate whether the use of LMWD for OCT is protective against kidney injury in patients with advanced renal insufficiency.METHODS In this retrospective cohort study,we identified 421 patients with advanced renal insufficiency (estimated glomerular filtration rate ＜ 45 mL/min/1.73 m2) who underwent coronary angiography or percutaneous coronary intervention;79 patients who used additional LMWD for OCT imaging (LMWD group) and 342 patients who used contrast medium exclusively (control group).We evaluated the differences between these two groups and performed a propensity score-matched subgroup comparison.RESULTS The median total volume of contrast medium was 133.0 mL in the control group vs 140.0 mL in the LMWD group.Although baseline renal function was not statistically different between these two groups,the LMWD group demonstrated a strong trend toward the progression of renal insufficiency as indicated by the greater change in serum creatinine level during the 1-year follow-up compared with the control group.Patients in the LMWD group experienced worsening renal function more frequently than patients in the control group.Propensity score matching adjusted for total contrast media volume consistently indicated a trend toward worsening renal function in the LMWD group at the 1-year follow-up.Delta serum creatinine at 1-year follow-up was significantly greater in the LMWD group than that in the control group [0.06 (-0.06,0.29) vs -0.04 (-0.23,0.08) mg/dL,P = 0.001],despite using similar contrast volume.CONCLUSION OCT using LMWD may not be protective against worsening renal function in patients with advanced renal insufficiency.

Key Words:Coronary artery disease;Kidney injury;Contrast media;Dextran;Optical coherence tomography;Renal insufficiency

INTRODUCTION

The presence of renal insufficiency has been reported to be associated with the increased risk of cardiovascular events[1].Contrast-induced acute kidney injury (AKI)is a contributing factor to poor outcomes after angiographic procedures[2-4].The incidence of contrast-induced AKI increases sharply as renal function decreases[5].Some patients may even experience a prolonged decrease in renal function late after the index procedure[6].Moreover,the presence of prolonged renal insufficiency in the long-term was associated with the increased risk of cardiovascular events[7].Renal insufficiency and the total contrast volume are widely known as risk factors for contrast-induced AKI[3,4].Thus,reducing total contrast volume during coronary angiography and/or percutaneous coronary intervention (PCI) is an important priority to prevent contrast-induced worsening renal function,particularly in patients with advanced renal dysfunction.

Recently,intracoronary optical coherence tomography (OCT) has been widely used to assess coronary plaque characteristics and optimize PCI in patients with coronary artery disease[8,9].OCT imaging requires blood displacement from the vessel lumen,and contrast media is the standard flushing agent,although the potential risk of contrast-induced AKI exists[2,3].Previous studies have demonstrated the feasibility of low-molecular-weight dextran (LMWD) as a safe alternative to contrast media for blood displacement during OCT imaging.Previous studies reported that OCT using LMWD might decrease the required total amount of contrast without losing image quality[10,11].On the other hand,LMWD-induced AKI has been repeatedly reported[12-15].Therefore,the protective role of LMWD against kidney injury remains uncertain in patients with advanced renal insufficiency,particularly regarding the long-term influence.

In the present study,we sought to investigate whether the additional use of LMWD for OCT imaging is protective against kidney injury in patients with advanced renal insufficiency undergoing coronary angiography and/or PCI by using propensity score-matched subgroup analysis during 1-year follow-up.

MATERIALS AND METHODS

Study population

This study was performed in compliance with our institutional ethics committee guidelines,and the study received its approval.All patients provided written informed consent before invasive coronary angiography or PCI for future data utilization.

In this retrospective cohort study,we identified 700 patients with advanced renal insufficiency [estimated glomerular filtration rate (eGFR) ＜ 45 mL/min/1.73 m2] who underwent diagnostic coronary angiography or PCI between March 2016 and June 2019 at Tsuchiura Kyodo General Hospital.The study period was chosen because,after March 2016,the total volume of injected flushing agents,including contrast medium and LMWD,was accurately documented by the use of an automated power injector.The final decision to perform an OCT examination by LMWD was at the operator’s discretion.Patients receiving maintenance dialysis were excluded from the analysis.Patients with insufficient data regarding the use of contrast/LMWD or follow-up renal function were also excluded from the analysis.Thus,the final analysis included 421 patients with advanced renal insufficiency,including 342 patients with contrast medium exclusively (control group) and 79 patients receiving additional LMWD for OCT imaging (LMWD group) (Figure 1).We compared patients’ clinical characteristics and the factors associated with renal function between these two groups using propensity score-matched subgroup analysis.All patient data and procedural details were obtained from patients’ medical records.

Coronary angiography and PCI

Each patient underwent diagnostic coronary angiographyviathe radial artery with a 5-French system,and PCI with a 6-French or 7-French system.A low-osmolarity contrast medium (iopamidol;Fuji Pharma Co.,Ltd.,Tokyo,Japan) was injected using an automated power injector (ACIST CVi;ACIST Medical Systems Inc.,Eden Prairie,MN,United States) at a rate of approximately 3.0-4.0 mL/s.All patients undergoing PCI were treated by coronary drug-eluting stent implantation.To determine the appropriate stent size and obtain optimal stent expansion,we used online quantitative coronary angiography and intracoronary imaging,including OCT and intravascular ultrasound findings.The type of stent was chosen at the operator’s discretion,and the interventionist determined the PCI strategy.

OCT image acquisition

OCT images were acquired using frequency–domain OCT systems:Abbott OCT(ILUMIEN OPTIS;Abbott Vascular,Santa Clara,CA,United States) or Terumo optical frequency–domain imaging system (Lunawave;Terumo Corporation,Tokyo,Japan).The technique of OCT image acquisition has been described elsewhere[8].OCT imaging pullbacks were performed automatically by the dedicated devices while injecting the flushing agent,which was either contrast medium or LMWD-40 (Otsuka Pharmaceutical Factory,Inc.,Tokushima,Japan),at a flow rate of 3.0-4.5 mL/sviathe guiding catheter using an automated power injector.Pullback speed was 18 mm/s with the Abbott OCT system and 20 mm/s with the Terumo optical frequency-domain imaging system.

Renal function assessment

Laboratory data were sampled before coronary angiography and/or PCI at the protocol-specified timing for evaluating renal function.Morning fasting blood samples on the day of the procedure were obtained in patients undergoing elective procedures.In patients with acute coronary syndrome (ACS) and those undergoing urgent procedures,blood samples were obtained at admission.We calculated eGFR using the equation modified for Japanese patients:eGFR (mL/min/1.73 m2) = 194 × (serum creatinine)-1.094× (age)-0.287× 0.739 (for women)[16].Advanced renal insufficiency was defined as eGFR ＜ 45 mL/min/1.73 m2[17].

Contrast-induced AKI was defined as a ≥ 0.3 mg/dL increase in serum creatinine level from baseline within 5 d after the procedure[18].Worsening renal function in the long-term was defined as a ≥ 0.3 mg/dL increase in serum creatinine level from baseline to the 1-year follow-up[19].We evaluated the incidence of contrast-induced AKI and worsening renal function,and serial changes in serum creatinine level within 5 d,and at 1 mo and 1-year post-procedure.We defined delta creatinine (ΔCre) as the difference between post- and pre-procedural serum creatinine levels.Risks for contrast-induced renal dysfunction were stratified by the Mehran risk score[20].

Figure 1 The patient population in this study.

Hydration protocol

Our institutional standard protocol for hydration was applied in all patients undergoing elective procedures and in selected patients with ACS.Intravenous normal saline (1.5 mL/kg/h) was administrated for at least 3 h before contrast exposure after blood sampling for baseline renal function,and was continued for at least 12 h after the procedure.After the literature review,this protocol was approved by the institutional ethics committee on the condition of close clinical monitoring for signs of intolerance in patients with heart failure[21].

Statistical analysis

The statistical analysis was performed using R version 3.6.2 (The R Project for Statistical Computing,Vienna,Austria).Categorical data are expressed as absolute frequencies and percentages and were compared using theχ2test or Fisher’s exact test,as appropriate.Continuous variables are expressed as mean ± SD for normally distributed variables and median (25th-75thpercentile) for non-normally distributed variables.Analyses were performed with the Mann-WhitneyUtest for non-normally distributed variables.Changes in serum creatinine (baseline,5 d,1 mo,and 1-year post-procedure) were evaluated using one-way repeated measures analysis of variance.

To reduce the effect of bias regarding exposure to LMWD in this observational study,we adjusted for significant differences in patients’ baseline characteristics between the control and LMWD groups using propensity score-matched subgroup analysis.We applied propensity score-matched subgroup analysis,adjusted for age,sex,indication (coronary angiography or PCI),baseline eGFR level,and total contrast volume.The propensity score-matched subgroup analysis adjusted for these confounders was performed with a 1:1 algorithm using nearest-neighbor matching with a caliper width of ± 0.10 and no replacement.The effect of the additional use of LMWD on renal function was assessed between these propensity score-matched subgroups.The relationship between worsening renal function (dependent variable),flushing agent,and other potential confounders was evaluated using multivariate logistic regression analysis (stepwise forward method) to assess whether LMWD use remained associated with worsening renal function.The associated variables in the univariate analyses (P＜ 0.10) were entered into the propensity score-matched models.We used the Hosmer–Lemeshow test to establish the goodness-of-fit of the model,andP＞ 0.05 indicated that the model provided a valid representation.Receiver operating characteristic (ROC) curves were analyzed to determine the optimal cut-off values for the confounding variables to predict worsening renal function.A two-sidedP＜ 0.05 was considered statistically significant.

RESULTS

Patients’ baseline characteristics

The final analysis included 342 patients in the control group and 79 patients in the LMWD group (Figure 1).Patients’ characteristics in these two groups are shown in Table 1.The baseline eGFR level and the distribution of GFR categories were not different between the two groups.A median volume of 133.0 mL of contrast medium was used in the control group.In the LMWD group,a median LMWD volume of 67.6 mL for OCT imaging plus 140.0 mL of contrast medium was used.No anaphylactic reactions occurred.Hemodialysis was required in one patient in the control group during the 1-year follow-up.

Renal function post-procedure in the entire study cohort

The LMWD group demonstrated a strong trend toward the progression of renal insufficiency as indicated by the greater change in serum creatinine levels during the 1-year follow-up compared with the control group (Table 1,Figure 2A).Contrastinduced AKI occurred in 9 patients (11.4%) in the LMWD group and 42 patients(12.3%) in the control group (P= 1.000).However,patients in the LMWD group experienced worsening renal function more frequently than patients in the control group (Table 1).

Propensity score-matched comparisons

A propensity score-matched cohort adjusted for age,sex,indication (coronary angiography or PCI),baseline eGFR level,and total contrast volume yielded 150 (75 patients each in the control and LMWD groups) well-matched patients regarding potential confounding baseline variables for the clinical and procedural characteristics.A comparison of renal function after the procedure between the control and LMWD groups in the propensity score-matched cohort is shown in Table 2.The baseline eGFR level and the distribution of GFR categories were not different between the two groups.Moreover,no patients had GFR category 5 in the matched cohort.The incidence of contrast-induced AKI was not significantly different between the two groups.In contrast,the LMWD group demonstrated a strong trend toward the progression of renal insufficiency as indicated by the greater change in serum creatinine level during the 1-year follow-up compared with the control group (Table 2,Figure 2B).Although the prevalence of worsening renal function was not statistically different (25.3%vs12.0%,P= 0.059),ΔCre at 1-year follow-up was significantly greater in the LMWD group than that in the Control group [0.06 (-0.06,0.29)vs-0.04 (-0.23,0.08) mg/dL,P= 0.001],despite using similar contrast volume.ROC curve analyses demonstrated that the optimal cut-off values for LMWD volume and baseline eGFR level to predict worsening renal function were 52.0 mL for LMWD volume [area under the curve (AUC):0.614;95% confidence interval (CI),0.504-0.724] and 38.4 mL/min/1.73 m2for baseline eGFR level (AUC:0.654;95%CI:0.555-0.753).Multivariable logistic regression analysis revealed that the factors independently associated with worsening renal function were greater LMWD volume (≥ 52.0 mL)[odds ratio (OR):2.83,P= 0.019] and lower baseline eGFR level (＜ 38.4 mL/min/1.73 m2) (OR:4.27,P= 0.004) (Table 3).The Hosmer–Lemeshow test provided aPvalue of 0.993 in the matched cohort,which indicated a proper goodness-of-fit for this model.Moreover,greater LMWD volume particularly identified patients with a high risk for worsening renal function in worse baseline renal function (Figure 3).

Table 1 Patients’ characteristics and renal function (entire study cohort)

Data are presented as n (%) or median (25th-75th percentile).CABG:Coronary artery bypass graft surgery;CAD:Coronary artery disease;ΔCre:Delta creatinine;eGFR:Estimated glomerular filtration rate;LMWD:Low-molecular-weight dextran;LVEF:Left ventricular ejection fraction;NT-proBNP:Nterminal pro B-type natriuretic peptide;OCT:Optical coherence tomography;PCI:Percutaneous coronary intervention.

DISCUSSION

The main findings of the present study are:(1) The additional use of LMWD for OCT was identified in 18.8% (79/421) of the study patients with advanced renal insufficiency;(2) The LMWD group demonstrated a strong trend toward the progression of renal insufficiency as indicated by the greater change in serum creatinine level during the 1-year follow-up compared with the control group;(3)After propensity score matching,the LMWD group demonstrated a significant trend in the progression of renal insufficiency at the 1-year follow-up;and (4) Multivariable logistic regression analysis revealed that greater LMWD volume and lower baseline eGFR level were independently associated with worsening renal function in the propensity score-matched cohort.To the best of our knowledge,this is the first study to demonstrate that the additional use of LMWD for OCT imaging may not be protective against worsening renal function in patients with advanced renal insufficiency,particularly with respect to the long-term influence.

Impact of renal insufficiency for worse outcomes

Various studies have reported that renal insufficiency is independently associated with cardiovascular events and mortality[22-24].Notably,patients with eGFR ＜ 45 mL/min/1.73 m2were associated with a 1.49-fold increase in the risk of cardiovascular events compared with patients with eGFR ＞ 75 mL/min/1.73 m2,which resulted in a substantial reduction in life expectancy for patients with eGFR ＜ 45 mL/min/1.73 m2[25,26].Hypertension and diabetes mellitus are important causes of kidney dysfunction,which increase the risk of cardiovascular events.One of the mechanisms of cardiovascular complications in renal insufficiency involves endothelial dysfunction.Bajajet al[27]reported that coronary microvascular dysfunction was associated with impaired left ventricular mechanics and cardiovascular events in patients with chronic kidney impairment.

Contrast and LMWD for OCT imaging

OCT enables clear visualization of culprit and non-culprit plaque morphologies[8,9]and PCI optimization[28,29].LMWD is considered a safe alternative to contrast media for blood displacement during OCT imaging.Moreover,a recent study demonstrated that the changes in serum creatinine level just after the procedure did not differ between the patients treated with OCT guidance and those with intravascular ultrasound guidance,which included mainly normal and mild renal insufficiency[30].However,these previous studies enrolled a relatively small number of patients,and sample sizes were too small to draw definitive recommendations for the safety of additional use of LMWD for OCT in patients with advanced renal insufficiency.In contrast,our study involved a much larger number of patients with advanced renal insufficiency receiving LMWD additionally as a substitute flushing agent.In daily clinical practice,the additional use of LMWD for OCT has been preferentially performed in patients with advanced renal insufficiency to reduce the total contrast volume and prevent contrast-induced AKI.However,the safety of LMWD over contrast medium against kidney injury,particularly over the long-term,has not been fully studied.To our knowledge,our study is the first report examining the possibility of LMWD-related kidney injury when LMWD is used for OCT combined with contrast medium in patients with advanced renal insufficiency during a 1-year follow-up.

LMWD and renal impairment

In the previous studies that reported the association between LMWD and AKI[12-15],the total LMWD volume was much greater than that used for OCT because LMWD was used mainly to correct hypovolemia as a substitute for plasma concentrate.In contrast,in our study,the LMWD group showed a strong trend toward worsening renal function at the 1-year follow-up,after propensity score-matched comparisons,even though LMWD volume for OCT was a median of 68.5 (43.9,86.0) mL.The pathogenesis of contrast-induced AKI involves several mechanisms,such as nephrotoxic effects on tubular epithelial cells,tubular obstruction,decreased renal perfusion,and renal vasoconstriction[4].Osmotic nephrosis characterized by vacuolization and swelling of proximal tubular cells is induced by many substrates such as contrast medium and LMWD[15].LMWD is also associated with hyperoncotic kidney injury[13].Excretion of LMWD particles could be reduced,particularly in the presence of renal insufficiency.In previous studies,approximately 70% of LMWD was excreted by the kidneys within 24 h,while the remaining LMWD was excreted over several days[14,31].Administration of LMWD accompanied by a certain amount of contrast medium could potentially cause prolonged renal insufficiency in the longterm.

Table 2 Patients’ characteristics and renal function (matched cohort)

Data are presented as n (%) or median (25th-75th percentile).CABG:Coronary artery bypass graft surgery;CAD:Coronary artery disease;ΔCre:Delta creatinine;eGFR:Estimated glomerular filtration rate;LMWD:Low-molecular-weight dextran;LVEF:Left ventricular ejection fraction;NT-proBNP:Nterminal pro B-type natriuretic peptide;OCT:Optical coherence tomography;PCI:Percutaneous coronary intervention.

Table 3 Univariable and multivariable logistic regression model for predicting worsening renal function (ΔCre ≥ 0.3 mg/dL/1-year) in matched cohort

Figure 2 Serial comparison of serum creatinine levels at baseline,and within 5 d,1 mo,and 1-year post-procedure.

Figure 3 Prevalence of worsening renal function stratified by the cut-off values for low-molecular-weight dextran volume and baseline estimated glomerular filtration rate level in propensity score-matched cohort.

Clinical implications

The present study indicated that the additional use of LMWD in patients with advanced renal insufficiency showed a strong trend toward renal impairment at the 1-year follow-up.Our results also suggested that greater LMWD volume may be a contributing factor to the progression of long-term renal dysfunction in patients with advanced renal insufficiency.Excessive use of LMWD in place of contrast medium may not effectively decrease the prevalence of renal impairment after OCT imaging.

Our results,including the propensity score-matched comparison,suggest that using LMWD for OCT in patients with advanced renal insufficiency should be avoided,or at least care should be exercised to reduce the amount of LMWD.The present study also suggested the importance of long-term follow-up of renal function after LMWD use for OCT imaging.Since our study is of hypothesis generating nature,further studies are needed to test this hypothesis.

Study limitations

First,this was a retrospective study from a single center with a relatively small sample size and,thus,has inherent limitations.Although we used propensity score matching to adjust for differences in patients’ baseline clinical characteristics,including renal function,the final decision regarding the choice of flushing agents for OCT was at the operator’s discretion,and selection bias cannot be canceled.Second,because we collected data from our institutional OCT registry,some patients with ACS underwent pre- and post-PCI OCT examinations for the culprit lesion,and some underwent OCT examination for the non-culprit lesion before or after culprit lesion assessment/treatment for the clinical research.This nature of the study cohort might have led to an increase in contrast medium and/or LMWD volume.Third,we did not evaluate the influence of medical therapy and clinical status post-procedure on the incidence of contrast-induced AKI and worsening renal function,which could have affected our results.Although this study evaluated the renal function only within 5 d,and at 1 mo and 1-year post-procedure,the mid-term effect of LMWD on renal function was not fully studied.Fourth,the prevalence and severity of proteinuria and the cause of renal insufficiency were not assessed,and both could be closely related to the progression of renal dysfunction.Finally,we did not assess clinical outcomes or perform extensive subgroup analyses because of the relatively small number of events.

CONCLUSION

In this retrospective study,we observed the greater extent of the progression of renal dysfunction and the higher prevalence of worsening renal function,particularly at the 1-year follow-up,in patients with advanced renal insufficiency who underwent OCT imaging using LMWD.These findings provide a novel insight regarding LMWD use by interventionalists who are involved in OCT examinations.Further large,prospective studies are warranted.

ARTICLE HIGHLIGHTS

Research background

Low-molecular-weight dextran (LMWD) is considered a safe alternative to contrast media for blood displacement during optical coherence tomography (OCT) imaging.On the other hand,LMWD-induced acute kidney injury has been repeatedly reported.

Research motivation

The protective role of LMWD against kidney injury remains uncertain in patients with advanced renal insufficiency,particularly regarding the long-term influence.

Research objectives

To investigate whether the use of LMWD for OCT is protective against kidney injury in patients with advanced renal insufficiency.

Research methods

In this retrospective cohort study,we identified 421 patients with advanced renal insufficiency (estimated glomerular filtration rate ＜ 45 mL/min/1.73 m2) who underwent coronary angiography or percutaneous coronary intervention;79 patients who used additional LMWD for OCT imaging (LMWD group) and 342 patients who used contrast medium exclusively (control group).We evaluated the differences between these two groups and performed a propensity score-matched subgroup comparison.

Research results

Although baseline renal function was not statistically different between these two groups,the LMWD group demonstrated a strong trend toward the progression of renal insufficiency as indicated by the greater change in serum creatinine level during the 1-year follow-up compared with the control group.Patients in the LMWD group experienced worsening renal function more frequently than patients in the control group.Propensity score matching adjusted for total contrast media volume consistently indicated a trend toward worsening renal function in the LMWD group at the 1-year follow-up.Delta serum creatinine at 1-year follow-up was significantly greater in the LMWD group than that in the control group [0.06 (-0.06,0.29) vs -0.04 (-0.23,0.08) mg/dL,P = 0.001],despite using similar contrast volume.

Research conclusions

Additional use of LMWD for OCT may not be protective against worsening renal function in patients with advanced renal insufficiency.

Research perspectives

Since our study is of hypothesis generating nature,further large,prospective studies are warranted.