| Abstract|| |
Elevated plasma lipoprotein (LPa) level in chronic renal failure patients is recognized as an independent risk factor for premature atherosclerotic coronary heart disease. In this crosssectional study we aimed to study the effect of serum plasma LPa levels on early structural atherosclerotic vascular changes in chronic renal failure (CRF) predialysis and hemodialysis (HD) populations. We evaluated the carotid intima-media thickness and carotid-femoral artery for plaque occurrence (plaque score) by B-mode ultrasonography in 29 (17F, 12M) normal subjects (group one), 33 (19F, 14M) CRF predialysis patients (group 2) and 43 (19F, 24M) HD patients (group 3). The Mean LPa in group 1,2 and 3 were 42.0 ± 20.0, 57.0 ± 23.0 and 55.0 ± 16.0 mg/dl, respectively (p=0.016). The Intimae- media thickness (IMT) of group 1, 2 and 3 was 0.84 ± 0.20 1.30 ± 0.40 and 1.10 ± 0.30 mm, respectively (p<0.001). Plaque scores between 1 and 2 were found in 6.8% of the subjects in group 1, 24.3% in group 2 and 25.6% in group 3 (p<0.001). Furthermore, plaque scores of 3 and 4 were found in no subjects in group 1, 36.4% in group 2 and 23.3% in group 3. In conclusion; the present study showed positive relationship of LPa with IMT and arterial plaque in HD patients but not the CRF patients. However, accelerated atherosclerosis is frequently seen in these patients and larger clinical studies of this problem are needed.
Keywords: Intima, media, Lipoprotein (a), Hemodialysis, Chronic renal failure, Plaque score.
|How to cite this article:|
Nasri H, Baradaran A. Association of Early Atherosclerotic Vascular Changes with Serum Lipoprotein (a) in Predialysis Chronic Renal Failure and Maintenance
Hemodialysis Patients. Saudi J Kidney Dis Transpl 2005;16:154-60
|How to cite this URL:|
Nasri H, Baradaran A. Association of Early Atherosclerotic Vascular Changes with Serum Lipoprotein (a) in Predialysis Chronic Renal Failure and Maintenance
Hemodialysis Patients. Saudi J Kidney Dis Transpl [serial online] 2005 [cited 2019 Nov 18];16:154-60. Available from: http://www.sjkdt.org/text.asp?2005/16/2/154/32934
| Introduction|| |
High level of plasma lipoprotein (a) (LPa) is recognized as an independent risk factor for premature atherosclerotic coronary heart disease.  In renal failure, studies revealed an increase in plasma concentration of LPa. ,,
Elevated plasma Lpa level in chronic renal failure patients has been associated with a frequency distribution of apolipoprotein (a) (APOa) isoforms; similar to those found in the general population. This indicates that elevated LPa level in these patients is not due to genetic variation. ,, Therefore, it has been suggested that kidneys have an important role in LPa metabolism, decrease LPa catabolism or increase liver production. ,,, Increased LPa levels could be a contributing factor in the increased incidence of atherosclerotic disease observed in CRF and hemodialysis patients. , The early stages of artherosclerosis are associated with changes in arterial structure. Subtle structural changes such as thickening of arterial intima-media complex thickness (IMT) occur early in the atherosclerotic disease process. ,, B-mode ultrasonography is a safe and noninvasive tool for assessing early atherosclerosis and to study superficial vascular districts, such as the carotid or femoral artery. ,, Ultrasonic evaluation of carotid artery for IMT can identify patients at risk for cardiovascular disease. ,, Indeed carotid arteries are an accessible area for studying the progression of atherosclerotic lesions from onset to fully developed plaque. Carotid IMT measurements are strongly related to the extent of atherosclerosis in other vascular districts too. ,,, Consistent with their accepted role in atherogenesis, many known and conventional risk factors have been shown to be significantly associated with increased arterial wall thickness. However, much less is known about the effects of LPa on IMT of CRF and hemodialysis (HD) patients. 
In this study, we primarily aim to consider the effect of plasma LPa levels on early structural atherosclerotic vascular changes in a group of CRF patients not yet on dialysis and in endstage renal disease patients under hemodialysis and we secondarily aim to consider the correlation of the IMT of the carotid artery and plaques of the carotid-femoral artery with other lipids and duration of disease.
| Patients and Methods|| |
This is a cross-sectional study that was done on patients with chronic renal failure not yet on dialysis and in end-stage renal disease patients undergoing maintenance HD treatment between September 2002 and December 2003.
The patients' exclusion criteria included cigarette smoking, body mass index more than 25, hypolipidemic drug intake, recent MI and vascular diseases as well as active or chronic infection and diabetes mellitus. Group 1 was composed of healthy persons who had no history of hypertension or renal disease, group 2 of chronic renal failure (CRF) patients not yet on hemodialysis and group 3 of regular chronic HD patients.
The subjects in group 1 were interviewed using a questionnaire prior to consent in order to ascertain that they were free from any clinical evidence or history of diabetes, cardiac or vascular disease and had no past or current history of hypertension or any renal disease. Medical records of hospital determined the clinical history of patients in groups 2 and 3. Ninety-eight percent of the patients in groups 2 and 3 were on antihypertensive therapy and their blood pressure was under control.
The laboratory investigations included blood sampling after 14 hour overnight fasting (for group 1 and 2 done from antecubital vein and for group 3 at the beginning of the dialysis session). The following blood tests were obtained: fasting blood sugar (FBS), LPa, triglyceride (TG), cholesterol (C), high-density lipoprotein (HDL-C), Low-density lipoprotein (LDL-C), blood urea nitrogen BUN and creatinine (Cr.). LPa was measured by enzyme immunoassay (ELISA) (Immuno-biological laboratories (IBL) kit of Hamburg) other lipids mentioned above and BUN, Cr. and FBS were measured by standard kits. Serum LDL-C was calculated by Friedewald's formula.  Creatinine clearance was evaluated from serum creatinine, age and body weight. 
A single sonographer unaware of history or laboratory data of patients did carotid and femoral artery sonography using a HondaHs-2000 Sonograph with a 7.5 MHZ linear probe. The IMT in mm was measured and carotid-femoral arterial plaque score was determined. The measurements were done at the end of diastolic phase and the sites sampled were at the distal common carotid artery, area of bifurcation and at the first proximal internal carotid artery; IMT was measured at the plaque free areas. Subjects were in supine position with neck hyperextension and rotation of head to facilitate performance of the procedure.
The IMT was defined as the distance from leading edge of lumen-Intima interface of the far wall to the leading edge of the mediaadventitia interface of the far wall. IMT more than 0.8 mm was considered abnormal. For statistical analysis we considered the mean of the IMT of the right and left carotid artery.
Sonography for plaque detection was done at the right and left carotid and femoral arteries and scored from 0 (no plaque) to score 4 (plaque presence at all four sites) regardless of the number and size of the plaques. In each site, plaque occurrence was scored one point. The plaque was defined as a local intimal thickness more than 1 mm. For plaque measurement the largest longitude was considered.
| Statistical Analysis|| |
Descriptive data were expressed as Mean ± standard deviation (SD) and frequency distributions. For comparison between groups, ANOVA, Scheffe and Chi-Square tests were used. For correlations, partial correlation test after adjustment for age and the duration on HD was used and all statistical analysis were performed using SPSS (version 11.00) program. Probability (p) level < 0.05 was considered significant.
| Results|| |
The study patients included 29 (17F, 12M) normal subjects (group one), 33 (19F, 14M) CRF predialysis patients (group 2) and 43 (19F, 24M) HD patients (group 3).
[Table - 1] shows the demographic data and results of investigations and measurements of the IMT of carotid arteries in the study subjects. The mean duration of disease in group 2 and the duration on HD in group 3 were 36 ± 20 and 44 ± 31 months, respectively. The mean creatinine clearance of group 2 and group 3 were 31±18 and < 10 ml/min, respectively. The mean IMT in group 1, 2 and 3 were 0.84 ± 0.20, 1.30 ± 0.40 and 1.10 ± 0.30 mm, respectively. There was significant difference of IMT (p<0.001), significant difference of IMT between group 1 and 2, (p<0.001) and between group 1 and 3, (p=0.008) was found. Furthermore, there was a significant difference of IMT between group 2 and 3, (p=0.023).
[Table - 2] shows the mean ± SD of lipids profile in the study subjects. The mean LPa in group 1, 2 and 3 was 42.0 ± 20.0 and 57.0 ± 23.0 and 55 ± 16 mg/dl, respectively. There was a significant difference of LPa between group 1 and 2, (p=0.016) as well as group1 and 3, (p=0.021). No significant difference of TG and HDL-C between the three groups were found (p>0.05), while there were significant differences between the three groups in the LDL-C (p<0.001) level and total cholesterol (p<0.001).
[Table - 3] shows the frequency distribution of plaque score in the study subjects. Zero plaque score was found in 93%, 39.4% and 51.2% subjects in group 1, 2 and 3, respectively, while score between 1 and 2 was detected in 6.8%, 24.3% and 25.6% of subjects in group 1, 2 and 3 respectively. Furthermore, plaque score between 3 and 4 was found in 0%, 36.4%, 23.3% in group 1, 2 and 3 respectively. All the plaques were calcified. There was a significant difference between group 1 and 2 (p<0.001), and group 1 and 3 (p=0.02). How-ever, no significant difference of plaque score of group 2 and 3 was found, (p>0.05).
We compared the creatinine clearance with other variables in the groups of the study. We found a significant linear inverse correlation of creatinine clearance with LPa in the group 2 (r = -0.441, p= 0.040), [Figure - 1], while there was no correlation of creatinine clearance with IMT or plaque score in the different groups.
We compared the IMT and the lipids profile in the different groups. In group 1, significant positive correlation of IMT with LDL-C (r =0.350, p= 0.03) and significant linear inverse correlation of IMT with HDL-C (r = -0.405, p= 0.02) as well as marginal correlation of with triglycerides (r =0.310, p= 0.05) were found. However, no significant correlation of IMT with LPa and total cholesterol were found. In groups 2 and 3 there were no positive correlations of IMT with LDL-C, HDL-C, cholesterol and triglycerides. However, we found a significant positive correlation of IMT with LPa (r =0.298, p= 0.029) in group 3 [Figure - 2], while we did not find such correlation in group 2.
We compared the plaque score with the other variables in the study. We found no correlation between plaque score and IMT in group 1 and 3, while there was a significant positive correlation in group 2 (r =0.50, p= 0.002). There was no correlation between plaque score and serum LPa, LDL-C, HDL-C, Cholesterol or triglycerides in groups 1 and 2, while a significant positive correlation of plaque score with LPa (r =0.375, p= 0.008) was found in group 3, [Figure - 3].
| Discussion|| |
The findings of this study showed higher serum levels of LPa, more IMT and more plaque scores in chronic renal failure patients either predialysis or on HD than normal controls, with positive correlation of serum LPa with IMT and plaque score in hemodialysis patients only.
Pascazio et al. observed a large number of vascular plaques in uremia patients and concluded that the process of advance atherosclerosis might be started with the commencement of renal failure; he suggested that there are other factors than HD treatment to accelerate arthrosclerosis.  Damjanovic et al. evaluated IMT of 45 dialysis patients found higher mean carotid IMT in HD patients than in control group; also showed positive correlation of IMT with certain risk factors for atherosclerosis (age, duration of dialysis and lipid parameters).  Shoji and Hojs et al found no clear correlation of IMT with duration of hemodialysis treatment. , Hojs et al also found that age was the only significant determinant of number of plaques and concluded that HD patients had advanced atherosclerosis in the carotid arteries compared with normal subjects.  Moreover, Hojs in a recent study, showed no difference in plaque score between HD patients with CRF patients not yet on HD.
Savage et al noted more prevalence of plaque in carotid and femoral artery in HD and correlation between femoral artery plaque score and age of the subjects as well as correlation of age with IMT of carotid artery.  Recently, Kato et al showed a significant correlation of IMT with age in HD patients.  Moreover, Papagianni et al showed a positive correlation of plaque score with age of the subjects. 
Studies concerning the effect of LPa on IMT of normal persons showed various results. Sramek et al found no increased IMT in the carotid or femoral artery at high levels of LPa in asymptomatic men and concluded that LPa level was not associated with early atherosclerotic vessel wall changes in the carotid or femoral arteries.  Dentil et al, in a study on elderly subjects (mean age 78 years), showed no association between carotid IMT and LPa and concluded that the LPa was unrelated to the severity of atherosclerosis in the extra cranial vessels,  while Baldassarre et al found increased IMT of carotid in hypercholesterolemic patients with plasma LPa levels > 30 mg/dl than in those with moderate hypercholesterolemia or normocholesterolemic subjects.  Finally, Raitakari suggested no association between IMT and LPa in healthy subjects but found significant positive correlation with total cholesterol, LDL-C, LDL/HDL ratio, age, and triglycerides. 
In conclusion; the present study showed positive relationship of LPa with IMT and arterial plaque in HD patients but not the CRF patients. However, accelerated atherosclerosis is frequently seen in these patients and larger clinical studies of this problem are needed.
| Acknowledgment|| |
We would like to thank DR. M. Mowlaie (sonologist) who performed and interpreted the ultrasound of the carotid and femoral arteries.
| References|| |
|1.||Raitakari OT, Adams MR, Celermajer DS. Effect of Lp (a) on the early functional and structural changes of atherosclerosis. Arterioscler Thromb Vase Biol 1999;19: 990-5. |
|2.||Orem A, Deger O, Kulan K, et al. Evaluation of lipoprotein (a) as a risk factor for coronary artery disease in the Turkish population. Clin Biochem 1995;28:171-3. |
|3.||MBewu AD, Durrington PN. Lipoprotein (a): Structure, properties and possible involvement in thrombogenesis and atherogenesis. Atherosclerosis 1990;85:1-14. [PUBMED] |
|4.||Kimak E, Solski J, Janicka L, Duma D, Zagojska M. Plasma lipoproteins in patients with chronic renal failure. Int Urol Nephrol 1997;29:597-601. [PUBMED] |
|5.||Greiber S, Wanner C. Lipoprotein (a) in nephritic syndrome and end-stage renal disease. Miner Electrol Metab 1997;23: 161-5. |
|6.||Dieplinger H, Lackner C, Kronenberg F, et al. Elevated plasma concentrations of lipoprotein (a) in patients with end-stage renal disease are not related to the size polymorphism of apolipoprotein (a). J Clin Invest 1993;91:397-401. [PUBMED] [FULLTEXT]|
|7.||Kronenberg F, Trenkwalder E, Lingenhel A, et al. Renovascular arteriovenous in LP (a) plasma concentrations suggest removal of Lp (a) from the renal circulation. J Lipid Res 1997;38:1755-63. [PUBMED] [FULLTEXT]|
|8.||Misra M, Reaveley DA, Cooper C, et al. Mechanism for elevated plasma lipoprotein (a) concentrations in patients on dialysis: turnover studies. Adv Perit Dial 1998;14:223-7. [PUBMED] |
|9.||Koda Y, Nishi S, Suzuki M, Hirasawa Y. Lipoprotein (a) is a predictor for cardiovascular mortality of hemodialysis patients. Kidney Int Suppl 1999;71:251-3. |
|10.||Quaschning T, Krane V, Metzger T, Wanner C. Abnormalities in uremic 0 lipoprotein metabolism and its impact on cardiovascular disease; Am J Kid Dis 2001; 38(4) Suppl:S14-S9. |
|11.||Rattazzi M, Puato M, Faggin E, Bertipaglia B, Grego F, Pauletto P. New markers of accelerated atherosclerosis in end-stage renal disease. J Nephrol 2003;16:11-20. |
|12.||Kato A, Takika T, Maruyama Y, Kumagai H, Hishida A. Impact of carotid atherosclerosis on long-term mortality in chronic hemodialysis patients. Kidney Int 2003;64:1472-9. |
|13.||Papagianni A, Kalovoulos M, Kirmizis D, et al. Carotid atherosclerosis is associated with inflammation and endothelial cell adhesion molecules in chronic haemodialysis patients. Nephrol Dial Transplant 2003;18:113-9. [PUBMED] [FULLTEXT]|
|14.||Benedetto FA, Mallamaci F, Tripepi G, Zoccali C. Prognostic value of ultrasonographic measurement of carotid Intima media thickness in dialysis patients. J Am Soc Nephrol 2001;12:2458-64. [PUBMED] [FULLTEXT]|
|15.||Longenecker JC, Coresh J, Marcovina SM, et al. Lipoprotein(a) and prevalent cardiovascular disease in a dialysis population: The Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study. Am J Kidney Dis 2003;42(1):108-16. |
|16.||Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of Lowdensity lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502. [PUBMED] [FULLTEXT]|
|17.||Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine Nephron 1976;16:31-41. |
|18.||Pascazio L, Bianco F, Giorgini A, Galli G, Curri G, Panzetta G. Echo color Doppler imaging of carotid vessels in hemodialysis patients: evidence of high levels of atherosclerotic lesions. Am J kidney Dis 1996;28(5):713-20. |
|19.||Damjanovic T, Dimkovic N. Dialysis as a risk factor for development of atherosclerosis. Med Pregl 2003;56(1-2):17-21. |
|20.||Shoji T, Emoto M, Tabata T, et al. Advanced atherosclerosis in predialysis patients with chronic renal failure. Kidney Int 2002;61(6):2187-92. |
|21.||Hojs R. Carotid intima-media thickness and plaques in hemodialysis patients. Artif Organs 2000;24:691-5. [PUBMED] [FULLTEXT]|
|22.||Hojs R, Hojs-fabjan T, Balon BP. Atherosclerosis in patients with end-stage renal failure prior to initiation of hemodialysis. Ren Fail 2003;25(2):247-54. |
|23.||Savage T, Clarke AL, Giles M, Tomson CR, Raine AE. Calcified plaque is common in the carotid and femoral arteries of dialysis patients without clinical vascular disease. Nephrol Dial Transplant 1998;13: 2004-12. [PUBMED] [FULLTEXT]|
|24.||Sramek A, Reiber JH, Baak-pablo R, Sturk A, Rosendaal FR. Lipoprotein (a) and ultrasonographically determined early atherosclerotic changes in the carotid and femoral artery. J Thromb and Haemost 2003;1:374-9. |
|25.||Denti L, Marchini L, Pasolini G , Baffoni MT, Ablondi F, Valenti G. Lipoprotein Lp(a) and cerebrovascular disease in the elderly: correlation with the severity of extracranial carotid atherosclerosis assessed by ultra-sonography. Acta Biomed Ateneo Parmense 1995;66(3-4):175-83. |
|26.||Baldassarre D, Tremoli E, Franceschini G, Michelagnoli S, Sirtori CR. Plasma lipoprotein(a) is an independent factor associated with carotid wall thickening in severely but not moderately hypercholesterolemic patients. Stroke 1996;27:1044-9. [PUBMED] [FULLTEXT]|
Consultant Nephrologist, Section of Hemodialysis, Shahrekord University of Medical sciences, Hajar Medical, Educational and Therapeutic Center, Shahrekord
[Figure - 1], [Figure - 2], [Figure - 3]
[Table - 1], [Table - 2], [Table - 3]