Distribution of Iliac Artery Calcification on Unenhanced Computed Tomography Scans Performed on Potential Recipients Prior to Renal Transplantation

Abstract

French

Purpose:

To investigate whether a significant difference exists between the calcification of the common iliac arteries (CIAs) and the external iliac arteries (EIAs) and test for associations between clinical factors and the distribution of calcification.

Methods:

A retrospective review of renal transplant candidates who underwent a routine preoperative unenhanced computed tomography yielded 214 patients. Agatston scores for the patients’ left CIA, left EIA, right CIA, and right EIA were assigned. A retrospective search of patient records screened for 5 clinical factors (diabetes, hypertension, coronary artery disease [CAD], smoking, and dialysis). Data were assessed using a 2-sided t test, odds ratio, and a multivariate linear regression calculated through generalized estimating equation (GEE).

Results:

The log-transformed Agatston scores in the CIA were found to be significantly greater than that in the EIA (t = 9.57, P < .0001), with a mean difference of 1.5078 (95% confidence interval: 1.1962-1.8194), indicating relative EIA sparing. There were no significant differences in calcification between the right and left sides. Generalized estimating equation found that CAD and smoking demonstrated independent positive associations with EIA sparing (GEE = 2.6464 [P = .0197] and 1.9092 [P = .0470], respectively). Age was also significantly associated and indicated that EIA sparing remained relatively constant throughout patients’ lives (GEE = 1.0711 [P < .0001]).

Conclusion:

This study has demonstrated statistically significant EIA sparing in end-stage renal disease patients and identified CAD and smoking as associated factors. This phenomenon warrants further investigation into its biological mechanisms and the impact of EIA sparing on outcomes following transplants.

Keywords

iliac calcification end-stage renal disease unenhanced computer tomography renal transplant eligibility

Introduction

Renal transplantation is the treatment of choice in end-stage renal disease (ESRD) as it leads to longer survival rates,¹ higher quality of life,^2,3 and lower costs³ when compared to treatment with dialysis. Before patients can receive access to treatment, they must first be deemed eligible for transplantation.

End-to-side anastomosis of the donor renal artery to the recipient external iliac artery (EIA) has been shown to be a preferable method of transplantation when compared to techniques such as end-to-end anastomosis of the donor renal artery to the recipient internal iliac artery.⁴ Specifically, it has demonstrated a lower rate of postoperative complications and better clinical outcomes.^4
-6

Calcification of the iliac arteries, which can interfere with end-to-side anastomosis, is commonly observed in patients with chronic kidney disease⁷ and is reported to be present in one quarter of renal transplant recipients.⁸ Patients with extensive calcification in their iliac arteries experience a higher rate of graft loss,^9
-11 reduced or delayed allograft function,^10,12 intraoperative complications,^11,12 and death with a functioning transplant.¹¹ Eligibility guidelines put forth by the Canadian Society of Transplantation recommend that patients with severe occlusive common iliac disease should not be considered as transplant candidates.¹³ In some cases, vascular surgical intervention is necessary prior to renal transplantation.^14,15

Some institutions implement pelvic imaging is a routine step in the pretransplant workup to ensure successful anastomosis.^16,17 Among ESRD patients who have undergone imaging prior to transplant, a significant difference has been observed in the degree of calcification between the common iliac arteries (CIAs) and the EIAs, with relative sparing of the EIA compared to the CIA.^12,18 Current literature on this phenomenon is sparse and there is no reference to it in the current guidelines.¹³ External iliac artery sparing may be an important consideration when determining whether a patient with iliac calcification is eligible for an end-to-side renal transplant.

The aim of this study is to test whether there is a significant difference between the calcification in the CIA and EIA of patients with ESRD and test for associations between clinical factors and calcification patterns. To the best of our knowledge, this is the first paper to investigate factors associated with EIA sparing in ESRD patients.

Methods

A retrospective case–control methodology was undertaken. Agatston scores of the CIA and EIA, and the difference between them, were the primary measures of outcome. The clinical factors examined in the study were the presence of diabetes (type I or type II diabetes mellitus), hypertension, coronary artery disease (CAD), smoking, and dialysis (peritoneal dialysis, hemodialysis via catheter, or hemodialysis via fistula/graft), and patient age.

Study Population

Data were collected using a single-center convenience sample of patients (N = 214) from St. Michael’s Hospital. The inclusion criteria required all patients to be potential renal transplant recipients who underwent unenhanced pelvic computed tomography (CT) scanning as part of routine pretransplant assessment between February 2015 and July 2017.

Patient ages ranged from 26 to 80 with a mean age of 58.4 ± 10.7; 65.4% of patients were male (N = 140) and 34.6% of the patients were female (N = 74); 45.8% of patients were positive for diabetes; 90.7% were positive for hypertension; 26.2% were positive for CAD; 34.1% reported to have smoked at some point in their lives; 91.6% were on a form of dialysis at the time of the CT scan. Table 1 provides a summary of patient characteristics.

Table 1.

Summary of Patient Characteristics.

Parameter	Subgroups	N	% or Mean ± SD
Age	NA	214	58.4 ± 10.7
Sex listed	Male	140	65.4
Sex listed	Female	74	34.6
Diabetes (type I or type II DM)	Positive	98	45.8
	Negative	106	49.5
	Unreported	10	4.67
Hypertension	Positive	194	90.7
	Negative	18	8.41
	Unreported	2	0.935
Coronary artery disease	Positive	56	26.2
	Negative	153	71.5
	Unreported	5	2.34
Smoking	Positive	73	34.1
	Negative	126	58.9
	Unreported	15	7.01
Dialysis (PD, catheter, or fistula/graft)	Positive	196	91.6
	Negative	17	7.94
	Unreported	1	0.467

Abbreviations: NA, not applicable; DM, diabetes mellitus; PD, peritoneal dialysis; SD, standard deviation.

Data Collection

Unenhanced pelvic CT scanning was conducted using 1 of 3 systems manufactured by General Electric Healthcare (Chicago, Illinois): GE Optima, GE VCT, and GE Revolution. The CT scans were examined by 2 blinded raters, 1 staff and 1 resident. Both raters used a 3.00-mm axial scan viewed on a soft tissue window. Calcification in the CIA was measured from the aortic bifurcation to the internal iliac origin. Calcification in the EIA was measured from the internal iliac artery origin to the origin of the inferior epigastric artery.

Common iliac artery and EIA calcification were measured with Agatston scores, a weighted score based on the highest density of calcification (score of 1 for 130-199 HU, 2 for 200-299 HU, 3 for 300-399 HU, and 4 for 400 HU and greater) then multiplied by the area of calcification. The Agatston score has demonstrated a 90% sensitivity in detecting arterial calcium as well as a strong interobserver agreement.¹⁹

Agatston scores were calculated with TeraRecon iNtuition Edition version 4.4.13.P4 software. Both raters independently assigned an Agatston score to the right CIA, left CIA, right EIA, and left EIA of each patient. Interobserver agreement was measured with intraclass correlation coefficient (ICC). The Agatston scores between the 2 raters had ICC values of 0.95823, 0.82768, 0.95826, and 0.95858, for left CIA, right CIA, left EIA, and right EIA, respectively, indicating strong interobserver agreement. The Agatston scores from the primary staff rater were used in data analysis.

A retrospective search of patient records from Soarian Clinical Access in St. Michael’s Hospital was conducted to collect data of clinical factors. The project received ethics approval by the Unity Health Toronto Research Ethics Board.

Measurements and Statistical Analysis

The study employed both parametric and nonparametric tests. The difference in Agatston scores between common and EIAs was evaluated using a 2-sided t test. The normality of the distribution was confirmed using a Q-Q plot. The Agatston scores for the left CIA, left EIA, right CIA, and right EIA were calculated separately. The raw Agatston scores among the patient sample did not follow a normal distribution. This was corrected for the parametric tests by converting the scores to a log scale.²⁰ Converting to a log scale allowed for a parametric t test to be used, which has higher power over nonparametric tests and allows for means to be compared instead of medians. Agatston scores of 0 could not be converted to this scale and were excluded from the sample as a result. Some patients had an Agatston score of 0 in an iliac artery on only one side, allowing for the CIA/EIA pair on their contralateral side to remain in the sample. After adjusting to a log scale, the difference in Agatston score between each CIA and its respective EIA was calculated (N = 143). The relationship between Agatston scores in the left and right iliac arteries was measured using a paired 2-sided t test and Pearson correlation coefficient.

The association between clinical factors and EIA sparing was tested with odds ratio (OR) and a multivariate linear regression calculated with a generalized estimating equation (GEE). Generalized estimating equation was also used to measure association between patient age and EIA sparing. The outcome measurement during tests of association was the difference between a patient’s CIA Agatston score and EIA Agatston score on both sides. A difference >0, indicating EIA sparing, was coded as a positive outcome, while a difference ≤0 was coded as a negative outcome. Some patient records did not record the presence or absence of certain clinical factors (Table 1), which precluded them from being included in certain tests of association.

The association of clinical factors with overall Agatston score was measured using a repeated measure analysis of covariance (ANCOVA), with an interaction term applied to any statistically significant results. The correlation between age and overall Agatston score was measured using Spearman rank correlation coefficient.

All statistical analyses were calculated using SAS. When testing significance, a P value <.05 was considered statistically significant. When testing for correlation coefficients, a ρ value <0.3 was considered weak, a value 0.3 to 0.8 was considered moderate, and a value >0.8 was considered strong.

Results

Difference in Log-Transformed Agatston Score Between the Common and EIAs

The log-transformed Agatston scores in the CIA were found to be significantly greater than that in the EIA (t = 9.57, P < .0001; Figure 1), with a mean difference of 1.5078 (95% confidence interval [CI]: 1.1962-1.8194). The results were unchanged after stratifying for the right and left sides. On the right (N = 72), there was a mean difference of 1.2924 (95% CI: 0.8557-1.7291; t = 5.90; P < .0001). On the left (N = 71), there was a mean difference of 1.7262 (95% CI: 1.2767-2.1758; t = 7.66; P < .0001).

The difference in mean Agatston score on the left and right sides was separately tested for CIA and EIA using a 2-sided t test. Neither demonstrated a significant difference (CIA, P = .0648; EIA, P = .2115), suggesting that the degree of iliac calcification is similar on both sides. Agatston scores on the left and right sides, with CIA and EIA scores being treated as a single sample, demonstrated a moderate positive correlation (Pearson ρ = 0.70164; P < .0001). This correlation further suggests that the degree of iliac calcification is relatively constant on both sides.

Association Between Clinical Factors and EIA Sparing

In the present OR and GEE models, the presence EIA sparing was defined by the difference between a patient’s CIA and EIA Agatston score on each side. A difference >0, indicating EIA sparing, was coded as a positive outcome, while a difference ≤0 was coded as a negative outcome.

The presence of CAD within the patient population had a significant positive association with EIA sparing, to similar degrees on both the right and left sides (Table 2). On the right side, OR = 2.5107 (95% CI: 1.1407-5.5259; P = .0222). On the left side, OR = 2.5556 (95% CI: 1.1962-5.4599; P = .0154). Inputting the data into the GEE model, which controls for covariates and aggregates the left and right sides, demonstrated similar results. It was found that, compared to the reference group of patients without CAD, those with the disease were 2.646 (95% CI: 1.1682-5.9954; P = .0197) times as likely to demonstrate EIA sparing (Table 3).

Table 2.

The Odds Ratios for Clinical Factors Against EIA Sparing.^a

Clinical Factor	OR (95% CI)	P Value
Left side
Diabetes (n = 205)	1.7230 (0.9445-3.1432)	.0761
CAD (n = 210)	2.5556 (1.1962-5.4599)	.0154^b
Dialysis (n = 214)	1.5983 (0.5807-4.3990)	.3639
Smoking (n = 200)	2.0930 (1.0804-4.0545)	.0286^b
Hypertension (n = 213)	0.8251 (0.2817-2.4163)	.7258
Right side
Diabetes (n = 205)	1.5405 (0.8349-2.8422)	.1667
CAD (n = 210)	2.5107 (1.1407-5.5259)	.0222^b
Dialysis (n = 214)	1.8537 (0.6715-5.1169)	.2335
Smoking (n = 200)	1.4049 (0.7329-2.6931)	.3059
Hypertension (n = 213)	0.4724 (0.1317-1.6941)	.2498

Abbreviations: CAD, coronary artery disease; CI, confidence interval; EIA, external iliac artery; OR, odds ratio.

^a Bolded 95% CI indicates that upper and lower bounds are on the same side of the line of no difference.

^b P < .05.

Table 3.

Analysis of GEE Parameter Estimates, Clinical Factors Against Overall EIA Sparing.^a

Parameter	Estimate	95% Confidence Interval	Significance Level (P Value)
Diabetes	1.0684	0.5571-2.0493	.8420
Hypertension	0.6652	0.1627-2.7180	.5702
CAD	2.6464	1.1682-5.9954	.0197^b
Smoking	1.9092	1.0085-3.6143	.0470^b
Dialysis	1.0595	0.2877-3.9020	.9307
Age	1.0711	1.0354-1.1080	<.0001^c

Abbreviations: CAD, coronary artery disease; GEE, generalized estimating equation.

^a Bolded 95% CI indicates that upper and lower bounds are on the same side of the line of no difference.

^b P < .05.

^c P < .01.

Smoking also demonstrated a positive association with EIA sparing among the patient sample, though the results only appeared significant on the left side (Table 2). On the left, OR = 2.0930 (95% CI: 1.0804-4.0545; P = .0286). The overall results remained significant in the GEE model (Table 3). Compared to the reference group of nonsmoker patients, those who smoked were 1.9092 (95% CI: 1.0085-3.6143; P = .0470) times as likely to demonstrate EIA sparing.

Within the GEE model, patient age was also found to be significantly associated with EIA sparing (Table 3). This association indicated that the likelihood of EIA sparing remained fairly constant throughout patients’ lives. Controlling for covariates, with each increase in age by 1 year, the odds of demonstrating EIA sparing was 1.0711 (95% CI: 1.0354-1.1080; P < .0001) times as likely as the previous year.

Association Between Clinical Factors and Overall Agatston Score

Preliminary ANCOVA results indicated that CAD and smoking were significantly associated with the overall Agatston scores in patients (Table 4). However, the significance of the results diminished after an interaction term was added to the 2 clinical factors in the model (Table 4). These results suggest that CAD and smoking are covariates to iliac calcification rather than independent predictors. Spearman correlation coefficients consistently demonstrated a significant weak positive correlation between age and overall Agatston score (Table 5).

Table 4.

Repeated Measure ANCOVA of Clinical Factors Against Overall Agatston Score.^a

Parameter	Estimate (F Value)	Significance Level (P Value)
Diabetes	0.40	.5271
Hypertension	0.93	.3359
CAD	10.79	.0013^b
CAD^c	2.67	.1065
Smoking	13.28	.0004^b
Smoking^c	0.05	.8317
Dialysis	0.70	.4046

Abbreviations: ANCOVA, analysis of covariance; CAD, coronary artery disease.

^aBolded 95% CI indicates that upper and lower bounds are on the same side of the line of no difference.

^b P < .01.

^c Interaction term transformation.

Table 5.

Correlation Between Age and Overall Agatston Score.

Side	Subgroup	Spearman Correlation Coefficient (ρ)	Significance Level (P Value)
Right side	CIA	0.39664	<.0001^a
	EIA	0.32035	<.0001^a
	Total	0.41098	<.0001^a
Left side	CIA	0.36520	<.0001^a
	EIA	0.30536	<.0001^a
	Total	0.37178	<.0001^a

Abbreviations: CIA, common iliac artery; EIA, external iliac artery.

^a P < .01.

Discussion

In this study, it was found that ESRD patients have a significantly less calcification in their EIAs compared to their CIAs. Although the literature on EIA sparing is currently sparse, this pattern has been observed in other samples of ESRD patients.^12,18 We found that the Agatston scores of the iliac arteries on the left and right side were positively correlated, indicating that the degree of calcification is similar on both sides. Allison et al²¹ examined the patterns of atherosclerosis in various vascular beds. It found that calcification in the left iliac arteries had a moderate correlation to calcification in the right iliac arteries and that the iliac arteries had the highest intrabed correlation of all vascular beds (r = 0.76). Their correlation coefficient is similar to the r = 0.70164 observed in the present study. Taken together, the data suggest that calcification on the right and left sides of the iliac arteries is relatively uniform.

We found EIA sparing to be positively associated with the presence of CAD and smoking. There is a breadth of literature that correlates smoking with the development of CAD,^22
-24 suggesting that the 2 factors’ association with EIA sparing may be linked. However, in the present study, smoking and CAD individually yielded statistically significant results in the GEE model employed. These results suggest that the 2 factors are independently associated with EIA sparing. An area of interest for future research is the specific relationship between smoking, CAD, and the presentation of EIA sparing. Investigating parameters such as the quantity and duration of smoking, and duration of CAD may yield further insights.

The likelihood of EIA sparing was found to be relatively constant regardless of age in the present patient sample. External iliac artery sparing has been observed in demographics outside of ESRD patients, such as in elderly populations.²⁵ Comparing the prevalence of EIA sparing in both ESRD patients and control groups of smokers/individuals with CAD that do not have ESRD as a comorbidity may yield further insights. Age was positively correlated with overall calcification. This is consistent with past reports across the literature.^12,18,26

Of the 5 clinical factors examined in the present study (diabetes, hypertension, CAD, smoking, and dialysis), none appeared to be significantly associated with the total Agatston score. However, the lack of significant correlations may have been due to limitations in the parameters used. Data were collected retrospectively through patient records. As a consequence, some parameters were left relatively broad. For instance, we did not differentiate between patients receiving peritoneal dialysis and those receiving hemodialysis (catheter or fistula/graft) nor did we quantify the time on dialysis. Past literature has found a correlation between the duration an ESRD patient is on hemodialysis and the total iliac vascular calcification.¹⁸ We also did not distinguish between patients with newly presenting diabetes and those with long-term histories. Past research has found that a history of diabetes for >10 years is associated with the degree of iliac calcification.²⁶

The present study’s case–control methodology also presents some limitations. Although an association between the 5 clinical factors and EIA sparing has been demonstrated, further testing with a different methodology is required to prove a causal relationship.²⁷ It is also difficult to confirm a temporal relationship between the clinical factors and onset of EIA sparing.²⁷

There are also limitations associated with assigning separate calcium scores for the CIA and EIA though CT imaging. In the present study, calcification in the CIA was measured from the aortic bifurcation to the internal iliac origin. Calcification in the EIA was measured from the internal iliac artery origin to the origin of the inferior epigastric artery. If an area of calcification crosses between the CIA and EIA boundary, the raters were required to subjectively divide a portion to each side. Furthermore, the origin of the inferior epigastric artery is often not well seen on unenhanced CTs if they are not calcified, making boundary assignment in these cases difficult. These factors may have hindered the precision of the data. Other potential confounders include the presence of artifact from metallic surgical clips adjacent to the EIA in patients who have had previous transplants, as well as proximity of arterial calcification to the subadjacent sacrum.

In summary, this study has demonstrated statistically significant relative EIA sparing in ESRD patients and identified CAD and smoking as associated clinical factors. This topic warrants further investigation on the biological mechanisms as well as the impact of EIA sparing on posttransplant outcomes.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Department of Urology, St. Michael’s Hospital (cost centre number 2-61-20151-27001). Adrian Marcuzzi received a stipend funded by the Urology department during his research period.

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