|Year : 2015 | Volume
| Issue : 3 | Page : 536-543
|Short-term effects of renal transplantation on coronary artery calcification: A prospective study
Pratyusha Priyadarshini1, Sandeep Aggarwal1, Sandeep Guleria1, Sanjiv Sharma2, Gurpreet Singh Gulati2
1 Department of Surgical Disciplines, All India Institute of Medical Sciences, New Delhi, India
2 Department of Cardiac Radiology, All India Institute of Medical Sciences, New Delhi, India
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|Date of Web Publication||20-May-2015|
| Abstract|| |
Cardiovascular disease is a leading cause of mortality in renal transplant recipients. Coronary artery calcification (CAC) has been found to have good correlation with atherosclerosis and cardiovascular morbidity. The objective of our study was to assess the prevalence of CAC and the long-term effects of renal transplantation on CAC and carotid intima-medial thickness (CIMT) in Indian renal transplant recipients. Twenty-eight renal transplant recipients were included in this prospective study. Dual-source computed tomography and calcium scoring using Agatston's method and CIMT measurement were performed at the time of transplant and then repeated at six and 12 months after transplantation. The prevalence of CAC in our study patients was low (32%), probably because they were young, had been on dialysis for a short duration and had undergone live-related renal transplant. An overall improvement in biochemical parameters was observed after transplantation. Patients with zero baseline calcium score did not show progression. Patients with baseline calcium score more than zero showed initial progression at 6 months and no further progression afterwards. There was good correlation between CIMT and CAC score. Our study suggests that renal transplantation does not reverse the calcification but appears to decrease the rate of progression in the long term.
|How to cite this article:|
Priyadarshini P, Aggarwal S, Guleria S, Sharma S, Gulati GS. Short-term effects of renal transplantation on coronary artery calcification: A prospective study. Saudi J Kidney Dis Transpl 2015;26:536-43
|How to cite this URL:|
Priyadarshini P, Aggarwal S, Guleria S, Sharma S, Gulati GS. Short-term effects of renal transplantation on coronary artery calcification: A prospective study. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2021 Jan 16];26:536-43. Available from: https://www.sjkdt.org/text.asp?2015/26/3/536/157359
| Introduction|| |
Renal transplant recipients are at a high risk of mortality from cardiovascular disease. Life expectancy has increased in recent years due to improved graft survival and, more recently, premature cardiovascular events have become the major cause of mortality in these patients.  At the time of renal transplantation, patients with end-stage renal disease have a huge burden of cardiovascular disease. Worsening of risk factors may occur in the post-transplant period due to the diabetogenic and atherogenic potential of immunosuppressive drugs. 
Although cardiac function tests are routinely performed in renal transplant recipients prior to surgery, coronary atherosclerosis can remain undetected. Coronary artery calcification (CAC) can be quantified using dual-source computer tomography and may improve the risk assessment of cardiovascular events in asymptomatic renal transplant recipients.  It has been reported that CAC, measured by electron beam computer tomography (EBCT), is predictive of cardiovascular morbidity and mortality in asymptomatic subjects. , Before the advent of EBCT measurement of CAC, measurement of the carotid intima-medial thickness (CIMT) with ultrasound, was considered as a reliable non-invasive technique of vascular imaging. ,,
Various studies have examined the effect of renal transplantation on CAC and CIMT in renal transplant recipients. However, there is paucity of similar studies in the Indian population.
| Subjects and Methods|| |
Twenty-eight patients aged >18 years, who had undergone living donor renal transplant within two weeks and had no previous history of coronary vascular event, were included in this study. Participants underwent detailed clinical, biochemical and radiological evaluation at baseline. All patients underwent repeat physical examination, biochemical analysis and imaging study at six-months and 12 months of follow-up.
Standardized questionnaire was used to obtain information about the cause of end-stage renal disease, duration and mode of dialysis, smoking history and medication usage for high blood pressure, high cholesterol or diabetes. Height and weight were measured in all participants and the body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Resting blood pressure was measured on three occasions with participants in the seated position. The average of the last two measurements was used in the final analysis. Hypertension was deemed present when the systolic pressure was ≥140 mm Hg, diastolic pressure was ≥90 mm Hg or if there was current use of anti-hypertensive medications.
In all subjects, a blood sample was collected after 8-12 h of overnight fast. The following investigations were performed: C-reactive protein (CRP), serum calcium and phosphate, alkaline phosphatase, albumin, fasting and postprandial blood sugar, urea/creatinine, urine microscopy and chemistry (for albuminuria) and lipid profile.
Lipid profile was measured using standard enzymatic methods. Dyslipidemia was considered to be present when the total cholesterol or triglycerides was higher than 240 mg/dL and 200 mg/dL, respectively.
Diabetes mellitus was diagnosed by fasting glucose >6.99 mmol/L (126 mg/dL) or use of hypoglycemic medication. Impaired fasting glucose was defined as fasting glucose levels of 6.11-6.94 mmol/L (110-125 mg/dL).
Measurement of coronary artery calcification using dual-source computerized tomography (CT) scan
All subjects underwent imaging on a dualsource CT scanner (Siemens' SOMATOM; Definition, Forchheim, Germany). This dual-source CT system uses two X-ray sources and two detectors at the same time. With 0.33 s/rotation, electrocardiogram-(ECG) synchronized imaging can be performed with 83-ms temporal resolution, independent of the heart rate, resulting in motion-free cardiac images. In this method, the calcium score is calculated by examining 3 mm tomographic slices of a patient's coronary artery tree to identify areas of calcified plaque, which is defined as lesions with a CT density of 130 Hounsfield units (HU) or more within an area of more than 1 mm 2 . The calcium score for each region of interest is determined by multiplying the calcified area by a density coefficient and the total calcium score is calculated by adding all the partial scores obtained in each region of interest. The intuitive syno-calcium scoring software was used for calculating the calcium score based on Agatston's principle. 
Coronary calcification score (Agatston's principle)
- Threshold CT density >130 HU for pixel areas >1 mm 2
- Lesion score
- 1 = 130-199,
- 2 = 200-299,
- 3 = 300-399,
- 4 = >400
- Score each region of interest by multiplying the density score and the area
- Total coronary calcification score was determined by adding up each lesion score for all sequential slices.
The CIMT measurement and scanning protocol followed the latest recommendation laid down by the Carotid Intima-Media Thickness Task Force, 2008. 
In all subjects, high-resolution B-mode ultrasound imaging of the common carotid arteries was performed with scanning on the longitudinal axis until the bifurcation and on the transverse axis. An instrument generating a wide-band ultrasonic pulse with a middle frequency of 7.5 MHz was used. A carotid plaque was defined as the presence of focal wall thickening that was at least 50% greater than that of the surrounding vessel wall or as a focal region with CIMT >1.5 mm that protrudes into the lumen and is distinct from the adjacent boundary.
| Statistical Analysis|| |
The data were prospectively collected and continually updated in the computer database. Statistical analysis was performed using Stata software, Stata Corp. Individual comparison of parameters at various intervals was analyzed using Student's "t" test. The correlation between variables was studied using non-parametric tests (Spearman's correlation test). P value <0.05 was considered significant.
| Results|| |
The mean age of the study population was 33 years (range = 19-58 years). The demographic profile of the study patients is depicted in [Table 1]. All patients were male and hypertensive. Of 28 patients, four (14.3%) were diabetic. Two patients (7.1%) were hepatitis B surface antigen positive and three patients (10.7%) were hepatitis C virus positive. All patients received hemodialysis prior to renal transplantation. The mean duration on dialysis was 9.43 months (range 5-20 months). There were no smokers.
All patients had a significant fall in mean systolic and diastolic blood pressures after transplantation, with a tendency for decreased requirement of anti-hypertensive drugs.
Changes in biochemical parameters
Significant changes were noted in calcium and phosphate levels toward normalization in the post-transplant period. The alkaline phosphatase, which was high at baseline, decreased to half. The calcium-phosphate product also decreased after transplantation. Overall, a significant improvement in calcium-phosphate metabolism was seen after renal transplantation; the values are summarized in [Table 2].
|Table 2: Biochemical parameters at baseline and at 6 and 12 months after renal transplantation.|
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The CRP levels decreased significantly after renal transplantation (P-value = 0.000) [Figure 1]. There was no significant change in the levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides in our patients during follow-up after renal transplantation.
|Figure 1: C-reactive protein levels in mg/L at baseline and 6 and 12 months after renal transplantation.|
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Changes in carotid intima-medial thickness
The mean CIMT was 0.074 mm and 0.052 mm in diabetic and non-diabetic patients, respectively. Using the sign rank test, it was found that diabetics had higher CIMT compared with non-diabetics. There was an increase in the CIMT in the first six months after transplantation. However, between six and 12 months, there was no significant increase in CIMT. There was no correlation between CIMT and blood pressure. A significant association was found between CIMT and calcium-phosphate product and LDL. However, no correlation was found with serum calcium, phosphate, HDL and CRP levels.
Dual-source CT scan
Of the 28 patients who underwent baseline dual-source CT scan, 19 had baseline Agatston's score of zero and there was no change in their calcium score six and 12 months after transplant. In patients who had baseline calcium score of more than zero, there was an increase in calcium score at six months after transplant. However, between six and 12 months, there was no significant increase in the calcium score.
After excluding the patients with zero calcium score, the average calcium score was 23.667 at baseline, which progressed to 32.89 at six months and 33.54 at 12 months of follow-up [Figure 2]. Thus, there was a significant increase of calcium score from zero to six months, but, after six months, there was no significant increase.
|Figure 2: Coronary artery calcification score at baseline and 6 and 12 months following transplantation.|
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No correlation was observed between blood pressure and coronary calcium scores. Also, no correlation was found between the calcium score, calcium, phosphate or calcium-phosphate product. We did find a correlation between LDL and calcium score; however, no correlation was found with HDL. In this study, the CIMT correlated well with the calcium score (correlation coefficient 0.521, P = 0.004).
| Discussion|| |
Coronary artery calcification in patients with end-stage renal disease is caused by uremia and increased serum calcium and phosphate levels. Kidney transplantation normalizes the serum phosphate and calcium levels. Hence, it may halt the progression of CAC. On the contrary, transplantation is associated with several atherogenic factors like immobilization, weight gain and loss of bone density. Thus, it remains unclear whether kidney transplantation ameliorates the progression of dialysis-associated CAC.
Two-thirds of our patients had zero calcium score at baseline and one-third had more than zero calcium score. This is in contrast to the findings of Raggi et al,  wherein CAC was demonstrated in 83% of 205 patients with an average age of 56.8 years. In various studies in the Western population, the prevalence of CAC has been found to be 50% or more. However, there are no studies on the prevalence of CAC in the Indian population. It has been shown that CAC score correlates with age, Caucasian race, dialysis duration and use of deceased donor organs. ,, Goodman et al  showed correlation of CAC with duration on dialysis. Oschatz et al  showed that CAC correlated with duration on dialysis and smoking. Our patient population was comparatively young (mean age 33 years), had been on dialysis for a short duration and underwent living donor renal transplantation. All of these factors might explain why the prevalence of CAC was low in our study.
An improvement in both systolic and diastolic blood pressures was observed in our study, which is similar to a recent study by Sylvia et al.  In our study, the CRP decreased significantly after renal transplantation. Mazzaferro et al  also reported a decrease in CRP, which is an acute phase marker of inflammation. This favorable change shows that, overall, there is a decrease in the inflammatory state after renal transplantation.
The calcium score, like other standard protocols, suffers from unavoidable measurement errors. To overcome this problem, Severukov et al  have recommended that for any given baseline measure of CAC, progression is determined if it exceeds the upper 95% confidence interval. In our study, we referred to the tables reported by Sevrukov et al. After six months of follow-up, it was found that there was an increase in the prevalence of CAC in our patients. However, between six and 12 months of follow-up, there was no further increase in CAC. Our results are similar to those of Oschatz et al, who have reported that dialysis-associated CAC progresses rapidly initially after transplantation but slows significantly during the later post-transplantation course. Transplantation therefore can be seen as a means to modify CAC in the long term. However, the baseline CAC scores in their group were higher and the study population was of the older age-group. 
Moe et al  found no significant progression of CAC 15-20 months after kidney transplantation. Similarly, Mazafferro et al  found that, after two years of renal transplantation, the Agatston's score was stable.
In our study, 19 of the 28 study patients had a baseline calcium score of zero. In a recent study by Roe et al,  112 renal transplant patients were followed-up for 18 months and only one-third of patients had a baseline calcium score of zero. Another one-third of their patients had a calcium score >400, while none of our patients had calcium score more than 400. They found that 25% of their patients showed progression of CAC score 18 months after renal transplantation. They also showed that mortality was higher in patients with higher calcium score and in patients whose calcium score progressed than in those with low calcium score and which did not progress.
In a similar study performed by Schankel et al,  electron-beam CT was performed on 82 subjects at the time of transplantation and repeated one year later. The mean and median CAC score showed an increase in all subjects from 392.4 and 75.8 at the time of transplant to 475.3 (P = 0.002) and 98.9 (P <0.001), respectively. Most subjects (89%) with no calcifications remained without calcification. Also, there was significant progression of CAC postrenal transplantation in most patients. They concluded that progression is most likely to occur in white patients and is associated with clinical factors such as blood pressure, body mass index, renal function and baseline CAC score.
In a study by Abedi et al,  the mean CAC score decreased significantly from 39.82 to 24.34 after transplantation. They concluded that renal transplantation significantly reduced CAC in patients with CKD. There was a linear correlation with decrease in parathormone levels and calcium-phosphate product at an early period after renal transplantation.
We did not find any significant association between CAC and serum calcium and phosphate levels. Although several studies have found an association between vascular calcification and serum calcium and phosphate levels, this has not been a universal finding. Braun et al  and Oschatz et al  could not show any such correlation, which is in agreement with our findings. Tamashiro et al  had found a correlation between high serum triglyceride and low HDL levels and progression of CAC.
A recent study  has shown that renal transplantation does not reverse or stop CAC. In this study, which included 150 renal transplant recipients, the prevalence of CAC increased from 35.3% to 64.6% and the mean score increased from 60.0 to 94.9 after 2.8 years of follow-up. Thirty-four patients with no baseline CAC converted to a positive score at follow-up, yielding an incidence rate of about 12.5% per year. [Table 3] summarizes the comparison of our study with various other studies.
|Table 3: Change in coronary artery calcification score after renal transplantation in various studies.|
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In our study, the mean baseline CIMT was 0.0584 cm. After six months, it was 0.0588 cm and after 12 months, it was 0.0589 cm. In diabetics, we found that the baseline CIMT was >0.07 cm and that three patients had CIMT more than 0.075 cm. CIMT correlated with patient's age. Nafar et al  showed a significant increase in CIMT after four and six months of renal transplantation. In our study also, we found progression of CIMT at six months. However, similar to the calcium score, there was no significant progression of CIMT after six months. We found that CIMT correlated with age and diabetic status. There was a strong positive correlation between CAC score and CIMT. Michael Nowicki et al  showed a strong correlation between CAC score and CIMT in 47 hemodialysis patients.
Okhuma et al  found a statically significant association between CIMT and serum calcium levels and CRP. We did not find any such correlation between CIMT and serum calcium and CRP. However, there was a significant correlation with calcium-phosphate product and LDL.
| Conclusion|| |
Renal transplantation results in favorable changes in calcium, phosphate, CRP and alkaline phosphatase levels. It does not stop or reverse the CAC. Although the CAC score showed progression in the early post-transplant period, it stabilized on longer follow-up. Progression of calcium score depends on the baseline calcium score, LDL level and calcium-phosphate product. The changes in CIMT are similar to the changes in CAC. Because calcification slows during the long term, early transplantation of patients with progressive CAC might be indicated.
| Limitations|| |
The small sample size and short duration of follow-up are the two major limitations of this study. A study with larger sample size and longer follow-up should be conducted to establish any future definitive recommendations.
Conflict of Interest: None
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Dr. Sandeep Aggarwal
Department of Surgical Disciplines, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 049
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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