|Year : 2021 | Volume
| Issue : 1 | Page : 30-41
|Prevalence of Vascular Calcification in Chronic Kidney Disease Stage 4 and 5 Patients and its Correlation with Inflammatory Markers of Atherosclerosis
Himanshu Verma1, Sham Sunder1, BB Sharma2, Neera Sharma3, Rashi Verma4
1 Department of Nephrology, Post Graduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, New Delhi, India
2 Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, New Delhi, India
3 Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, New Delhi, India
4 Department of Obstetrics, Institute of Gynecology and Obstetrics, Sir Gangaram Hospital, New Delhi, India
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|Date of Web Publication||16-Jun-2021|
| Abstract|| |
Vascular calcification is one of the independent risk factors associated with cardiovascular disease (CVD) in chronic kidney disease (CKD) patients. This study evaluated the prevalence of vascular calcification in Indian patients with CKD stages 4 and 5. This was a prospective study conducted between January 2011 and June 2012. CKD stage 4 and 5 patients of either sex aged >18 years were screened for aortic vascular calcification using digital X-ray lumbar spine and multislice computed tomography (CT) scan. In addition, details of inflammatory markers [high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL-6)] were also collected. A total of 150 patients (stage 4, n = 98; stage 5, n = 56) were screened for vascular calcification, and the mean age was 56.56 years. Patients with CKD stage 5 had significantly higher (P ≤0.05) serum creatinine and lower estimated glomerular filtration rate, total cholesterol, and low-density lipoprotein than CKD stage 4. Significantly, more patients with CKD stage 5 had a history of CVD. A total of 113 (75.3%) patients had vascular calcification [aortic calcification index (ACI) >0] with significantly higher prevalence in CKD stage 5 (85.72%) as compared to CKD stage 4 (69.15%). Patients having high aortic calcification (ACI >20%) were older (P = 0.0013); had a higher frequency of diabetes, and CVD; and had significantly (P <0.05) higher blood urea, serum creatinine, phosphorus, Ca × PO4 product, intact parathyroid hormone, hs-CRP, and IL-6. The higher CKD stage was associated with a higher prevalence of vascular calcification and higher aortic calcification index (ACI). CT techniques (electron beam CT and multislice CT) are the gold standards for detection and quantification of progression of vascular calcification.
|How to cite this article:|
Verma H, Sunder S, Sharma B B, Sharma N, Verma R. Prevalence of Vascular Calcification in Chronic Kidney Disease Stage 4 and 5 Patients and its Correlation with Inflammatory Markers of Atherosclerosis. Saudi J Kidney Dis Transpl 2021;32:30-41
|How to cite this URL:|
Verma H, Sunder S, Sharma B B, Sharma N, Verma R. Prevalence of Vascular Calcification in Chronic Kidney Disease Stage 4 and 5 Patients and its Correlation with Inflammatory Markers of Atherosclerosis. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2021 Jul 24];32:30-41. Available from: https://www.sjkdt.org/text.asp?2021/32/1/30/318546
| Introduction|| |
Chronic kidney disease (CKD) is one of the most common noncommunicable diseases in India with a significant burden on the healthcare system with a significant increase in morbidity and mortality. A recent systematic review and meta-analysis showed that the prevalence of CKD [according to the Modification of Diet in Renal Disease (MDRD) and CKD-Epidemiology Collaboration (CKD-EPI)] was 3% and 4%, respectively. CKD is a progressive and mostly irreversible disease, which is associated with several comorbidities. Based on estimated glomerular function rate (eGFR), the CKD is categorized into 5 stages (stage 1 to 5). In India, the prevalence of both CKD stages 4 and 5 has been shown be around 0.8%.
It is a known fact that eGFR starts decreasing as the CKD progresses which possibly results in decreased phosphorus excretion which may again lead to the development of hyper-phosphatemia. Hyperphosphatemia in patients with CKD is associated with secondary hyper-parathyroidism, and soft-tissue calcification (including vascular calcification). Cardiovascular disease (CVD) is one of the most important causes of morbidity and mortality among patients with CKD, and vascular calcification is one of the independent risk factors associated with CVD in both the general population and CKD patients. More than half of the patients with CKD die due to CVD even before reaching renal replacement therapy.,
There are several studies which showed the high prevalence of vascular calcification in patients with CKD;,,,,,, however, the data from India among CKD stages 4 and 5 are limited., Hence, this study was undertaken to evaluate the prevalence of vascular calcification in pre-ESRD (CKD stage 4 and 5) patients by measuring abdominal aortic calcification (AAC) using digital X-ray lumbar spine and multislice computed tomography (CT) scan.
| Methods|| |
This was a prospective study conducted between January 2011 and June 2012 at Post Graduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, New Delhi. Ambulatory patients of either sex aged more than 18 years with a confirmed diagnosis of stage 4 or 5CKD or hyperphosphatemia (serum phosphorus >4.6 mg/dL for CKD stage 4, and >5.5 mg/dL for CKD stage 5) were eligible for this study. Patients with ESRD who were on dialysis (hemodialysis or peritoneal dialysis), symptomatic coronary artery disease or arrhythmia, acute infection (defined by the presence of fever and/or leukocytosis) or chronic infection (hepatitis B or C and tuberculosis), acquired immunodeficiency syndrome, or previous renal transplantation were excluded from the study.
The study was conducted in accordance with the approved protocol, Good Clinical Practice Guideline of the International Conference on Harmonization, and principles that have their origin in the Declaration of Helsinki. The study protocol was reviewed and approved by the Institutional Ethics Committee. Each study participant provided written informed consent before participation in the study.
Eligible patients with CKD stages 4 and 5 were screened for aortic vascular calcification using digital X-ray lumbar spine and multislice CT scan. The following data were collected: demographics, basic diagnosis, medical history, duration of CKD, blood pressure, eGFR, current management, serum calcium, phosphorus, intact parathyroid hormone, 25-OH-Vitamin D3, alkaline phosphatase (ALP), albumin, and lipid profile. In addition, details of inflammatory markers [high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6)] were also collected. The eGFR was calculated using the MDRD formula.
The prevalence of vascular calcification was evaluated based on lateral lumbar digital X-ray, and multislice CT scan. Various factors predictive of vascular calcification were also evaluated. Lateral lumbar digital X-ray was performed in the standing position and calcification of the abdominal aorta was graded using a scoring system in which both the location and the severity of calcific deposits at each lumbar vertebral segment (L1–L4) were evaluated. The score was summarized as composite AAC score/Kauppila score [Figure 1]. Noncontrast 40-slice CT scan of the abdominal aorta was used to determine abdominal aortic calcification. CT scan of the abdominal aorta was performed with Philips Extended Brilliance Workspace [Figure 2]. Calcification was considered if an area ≥1 mm2 displayed a density ≥130 Hounsfield units. Aortic calcification index (ACI) was calculated by the radiologist. The ACI is used as a marker of the extent of aortic calcification. ACI ≥20%is an independent predictor for de novo cardiovascular events in CKD stages 4 and 5.
|Figure 1: Digital X-ray lumbar spine (lateral view) showing (a) pipestem aortic calcification (b) Kauppila scoring.|
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|Figure 2: Multislice computed tomography image of abdominal aorta showing multiple calcification sites.|
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Data were analyzed using SPSS Statistics 19. Data are expressed as means (standard deviation) (for normally distributed data), median, and interquartile range (IQR) or count and percentage. Continuous variables were compared with Student’s t-test. Categorical variables were compared with Fisher’s exact test. ACI was correlated with clinical characteristics and laboratory variables using Pearson’s correlation. Predictive factors for aortic calcification were first examined by univariate logistic regression analysis, and variables with a significant association (P <0.05) were included in multivariate logistic regression analysis (stepwise backward elimination). P<0.05 was considered statistically significant.
| Results|| |
A total of 150 patients were screened for vascular calcification. The mean age was 56.56 years, and 52% (n = 78) of patients were females [Table 1]. The mean eGFR was 18.84 mL/min/1.73 m2; a total of 98 patients had CKD stage 4 (eGFR, 15–29 mL/min/1.73 m2), and 56 patients had CKD stage 5 (eGFR, <15 mL/min/1.73 m2). The mean duration of CKD was 3.3 years. The primary kidney diseases were diabetic nephropathy (n = 65, 43.3%), chronic interstitial nephritis (n = 55, 36.7%), hypertensive nephropathy (n = 6, 4%), and others (n = 24, 16%). A total of 85 patients had diabetes mellitus, 122 (81.3%) had hypertension, and 63 (42%) had a history of cardiovascular disease (CVD). Overall, the mean systolic and diastolic BP was 133.6 mmHg and 81.21 mm Hg, respectively [Table 1].
Patients with CKD stage 5 were slightly older in age than patients with CKD stage 4 (P = 0.0199). Gender, blood pressure (systolic and diastolic), and duration of CKD did not differ significantly between CKD stage 4 and stage 5 [Table 1]. Patients with CKD stage 5 had higher significantly (P ≤0.0001) serum creatinine, blood urea, phosphorus, Ca × PO4 products, ALP, hs-CRP, and IL-6, and significantly higher intact PTH (P = 0.037). In addition, patients with CKD stage 5 had significantly lower eGFR (P <0.0001), hemoglobin (P<0.0001), 25 (OH)Vitamin-D3 (P = 0.0458), total cholesterol (P = 0.0060), and LDL (P = 0.0063). Significantly (P = 0.0019), more patients with CKD stage 5 (59%) had a history of CVD [Table 1].
A total of 113 (75.3%) patients had abdominal aortic calcification (ACI >0). The prevalence of vascular calcification in CKD stage 5 (85.72%) was significantly higher compared to CKD stage 4 (69.15%) (P = 0.0306) [Table 1]. Thus, patients with a higher CKD stage had a higher prevalence of vascular calcification. The patients with aortic calcification (ACI >0) were significantly (P <0.05) older and had significantly higher systolic BP, blood urea, serum creatinine, phosphorus, Ca × PO4 product, total cholesterol, LDL, intact PTH, hs-CRP, and IL-6; significantly (P <0.05) more patients had history of diabetes, hypertension, and CVD, and significantly lower eGFR (P = 0.0019) compared to patients without aortic calcification (ACI = 0) [Table 2].
|Table 2: Clinical and biochemical characteristics of patients with (aortic calcification index>0%) and without (aortic calcification index=0%) aortic calcification.|
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The median ACI was 17.15% (IQR, 6.25–20.8%) in all patients, 16.0% (IQR, 0.0–17.8%) in CKD stage 4, and 21.3% (IQR, 20.6–23.3%) in CKD stage 5. The ACI was significantly (P = 0.0001) higher in patients with CKD stage 5 compared to those with CKD stage 4 [Figure 3]. A total of 96 (64%) patients had Kauppila score ≥1 (on digital X-ray of lumbar spine). The mean (standard error, range) Kauppila score was 5.06 (0.37, 0–18) in all patients, 3.93 (0.36, 0–14) in CKD stage 4, and 7.01 (0.74, 0–18) in CKD stage 5. Kauppila score was significantly higher in patients with CKD stage 5 compared to those with CKD stage 4 (P = 0.0001). Thus, patients with a higher CKD stage had a higher Kauppila score. To identify predictors of high abdominal aortic calcification, patients were divided into cohorts with ACI ≥20% and <20%. The patients having high aortic calcification (ACI >20%) were older (P = 0.0013); had significantly (P <0.05) higher blood urea, serum creatinine, phosphorus, Ca × PO4 product, iPTH, hs-CRP, and IL-6; had higher frequency of diabetes, and CVD; and had significantly lower eGFR, hemoglobin, and serum albumin compared to patients having low aortic calcification (ACI <20%) [Table 3]. The patients with a history of CVD had higher calcification scores. Kauppila score was significantly higher (P <0.0001) in patients with high ACI >20% compared to patients with ACI <20%, thus Kauppila score correlates well with ACI [Figure 4].
|Figure 3: ACI for patients with CKD stage 4 and stage 5.|
The bold line in the box reflects the median. ACI: The upper and lower edges of the box show the 25th and 75th percentiles, respectively (IQR).
ACI: Aortic calcification index, CKD: Chronic kidney disease, IQR: Interquartile range.
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|Figure 4: Correlation plot of Kauppila score with aortic calcification index.|
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|Table 3: Clinical and biochemical characteristics of patients stratified by the extent of aortic calcification: High (aortic calcification index ≥20%) and low (aortic calcification index<20%).|
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Multivariate regression analysis identified the presence of diabetes and CVD, decreased eGFR, hyperphosphatemia, and inflammation as independent predictors of both the presence (ACI >0) and extent (ACI ≥20%) of abdominal aortic calcification, and older age and hyperparathyroidism as independent predictors of the presence of aortic calcification [Table 4] and [Table 5]. ACI was correlated with different clinical characteristics and biochemical variables using Pearson’s correlation and showed that ACI was negatively correlated with eGFR (r = -0.4643, P <0.0001) [Figure 5]. ACI was positively correlated with age (r = 0.4529, P <0.0001); serum phosphorus (r = 0.4554, P <0.0001); Ca × PO4 products (r = 0.4820, P <0.0001); intact PTH (r = 0.2702, P = 0.0008); hs-CRP (r = 0.785, P <0.0001); and IL-6 (r = 0.825, P <0.0001) [Table 6]. There was no significant correlation of ACI with serum calcium, ALP, 25-(OH)-Vitamin D3, and serum lipid profile.
|Figure 5: Correlation plot of estimated glomerular filtration rate with aortic calcification index for chronic kidney disease stage 4 and 5 patients|
ACI: Aortic calcification index, eGFR: Estimated glomerular filtration rate.
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|Table 4: Factors associated with the presence of abdominal aortic calcification (aortic calcification index>0).|
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|Table 5: Factors associated with high abdominal aortic calci fication (aortic calcification index≥20%).|
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|Table 6: Correlation of aortic calcification index with clinical and biochemical variables of chronic kidney disease stage 4 and 5 patients.|
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| Discussion|| |
This prospective study was conducted to evaluate the prevalence of vascular calcification patients with CKD stages 4 and 5, and results showed that the prevalence of vascular (abdominal aortic) calcification in patients with CKD stages 4 and 5 was 75%.The prevalence among CKD stage 4 was 69.5% and 85.72% in CKD stage 5.
The CKD is often complicated by vascular calcification particularly in patients with stages 4 and 5. The most common cause of death in CKD patients is CVD. Vascular calcification, particularly coronary artery and aortic calcification, is predictive of cardiovascular morbidity and mortality, especially in dialysis patients. The process of calcification generally starts in early stages of CKD. Although there are several studies which evaluated data regarding vascular calcification in CKD population,,,,,,, the literature on stages 4 and 5 from India is scarce., In previous CT studies, a higher prevalence of coronary artery calcification has been reported in patients with predialysis CKD, with a significant association between decreased GFR and CAC.,, The AAC has been reported to be associated with an increased risk of cardiovascular morbidity and mortality. Hence, in the present study, multislice CT and digital X-ray (lumbar spine) for semi-quantitative assessment of aortic calcification were used.
The prevalence of vascular calcification increases with advancing stages of CKD from 40% in patients with stage 3 CKD to 80–90% in patients with stage 5 CKD on dialysis.,, In the present study, the prevalence of vascular (abdominal aortic) calcification was around 75%, which was slightly lower than the previous series by Hanada et al (81%) and Toussaint et al (90%) among predialysis CKD patients.
In the present study, a higher CKD stage was found to be associated with a higher prevalence of AAC and the median ACI of 17.15% from the present study was comparatively lower than previous studies.,, Patients with CKD stage 5 had significantly higher ACI values compared to those with stage 4, and decreased eGFR was an inde-pendent risk factor for high AAC (ACI ≥20%). Overall, these and previous reports suggest a correlation between declining eGFR and vascular calcification.,,, A study by Valson et al, which included 710 predialysis stage 4 and 5 CKD patients attending nephrology outpatient clinic at a tertiary care hospital in South India and evaluated 558 lateral abdominal X-rays, found that the AAC was seen in only 6.8% of patients. Stage 4 CKD patients had a significantly (P = 0.03) higher prevalence of AAC (10% vs. 5.1%) than stage 5 CKD patients.
Both traditional cardiovascular risk factors and uremia-related risk factors, such as abnormalities in mineral metabolism, inflammation, and oxidative stress, contribute to the development of vascular calcification.,, CKD mineral and bone disorder (MBD)-related factors such as hyperphosphatemia, hyper-calcemia, high Ca × PO4 product, hyperpara-thyroidism, FGF-23, and klotho were considered to be associated with vascular calcification., However, the understanding of these parameters among patients not on dialysis is limited. In the present study, older age, diabetes, inflammation (high hs-CRP and IL-6), hyperphosphatemia, and hyperpara-thyroidism were found to be important risk factors for abdominal aortic calcification. Hanadaet al, have reported that older age, the presence of diabetes, and decreased e-GFR are independent predictors of the presence of aortic calcification.
In the present study, the prevalence of vascular calcification in patients with CKD (stage 4 or 5) who also had a history of diabetes was found to be 82.4%, which was slightly higher than Block et al (73%) and lower by Kramer et al (93%).
The present study also highlighted significantly low levels of albumin in patients with high AAC as compared to those with low AAC. These observations suggest that the presence of hypoalbuminemia, which is a prominent risk factor of malnutrition, is associated with progression of AAC in CKD patients. These observations are in concordance with previous studies.,
The authors also acknowledge the following limitations of the study. First, the sample size was relatively small, and second, the study was conducted at a single center, hence caution must be taken when generalizing the results. Further, multicentric studies with larger sample size may be needed to corroborate these findings.
To summarize, results from this study showed that around 75% of patients with CKD stages 4 and 5 had vascular calcification. The higher CKD stage was associated with a higher prevalence of vascular calcification and higher ACI. Older age, presence of diabetes and CVD, decreased eGFR, hyperphosphatemia, and inflammation were associated with the presence (ACI>0) and severity (ACI ≥20%) of AAC. CT techniques (electron beam CT and multislice CT) are the gold standards for detection and quantification of progression of vascular calcification. Digital X-ray is an inexpensive, semi-quantitative method to detect vascular calcification having a good correlation with CT scan. The sensitivity of digital X-ray for detecting vascular calcification is 85%. Despite few limitations, this study adds significant data to the literature, which could be helpful to in evaluating inflammation and cardiovascular risk among CKD patients.
Conflict of interest: None declared.
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Department of Nephrology, Post Graduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, New Delhi
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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