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Prevalence of atherosclerosis in renal transplant recipients
Abstract
Cardiovascular diseases are a major cause of morbidity and mortality after kidney transplantation. Renal transplant recipients have in fact accelerated atherosclerosis because of prolonged hemodialysis, arterial hypertension, dyslipidemia and other vascular risk factors. Studies concerning carotid and lower limb atherosclerotic changes in renal transplanted patients are at present scant.
In the present study the prevalence of carotid and iliac-femoro-popliteal atherosclerosis was evaluated by color flow Doppler in 99 patients 64 +/- 41 DS months after renal transplantation. Statistical analysis was used to correlate the presence and grade of atherosclerotic lesions with vascular risk factors and other clinical-laboratoristic parameters of the patients.
The overall incidence of atherosclerotic lesions in the population studied was 54.5%; 46.5% of patients presented atherosclerotic plaques at carotid district, 43.4% at lower limb arteries and 35.4% at both districts. Two of these patients were symptomatic; one patient affected by claudicatio intermittens was submitted to conservative therapy, whereas another patient with abdominal aortic aneurysm underwent to surgical treatment. Univariate analysis showed a significant difference between males and females for lower limb atherosclerotic lesions (p=0.0013), whereas no correlation was found between carotid lesions and sex, or between smoke and atherosclerosis. Significant correlations were found by multiple correlations analisys between: the grade of atherosclerotic lesions in both districts and the patient age (p<0.0001); the grade of carotid atherosclerotic plaques and duration of pretransplantation dialysis (p<0.01); the grade of lower limb atherosclerosis and respectively glicemic (p<0.01), hematocrit (p<0.01), potassium (p<0.002) values, systolic blood pressure (p<0.02).
Relevant rates of renal transplant recipients have carotid and peripheral atherosclerotic lesions. The study of aorto-iliac and lower extremity vascular atherosclerosis have important implications for the transplanted kidney functionality. Color flow Doppler represents a sensitive method for the follow-up examination of these patients.
Background
Despite remarkable improvement in renal function attributable to kidney transplantation, the burden of cardiovascular disease (CVD) among kidney transplant recipients (KTRs) remains high in the post-transplant period. Aggressive use of statins in KTRs may make lipoprotein ratios correlate better with atherosclerotic vascular disease (AsVD) when compared with traditional lipid profile parameters. We therefore evaluated the clinical and echocardiographic correlates of AsVD among non-diabetic, stable, black KTRs in South Africa.
Methods
This was a cross-sectional study of 41 adult (18–65 years), non-diabetic, stable KTRs and 41 age- and sex-matched healthy controls. An interviewer-administered questionnaire was used to obtain information on participants’ sociodemographic and cardiovascular risk factors. Anthropometric parameters were measured. Urine and blood samples were obtained and analyzed. Echocardiography was performed and carotid intima media thickness (CIMT) was assessed in both right and left carotid arteries. Spearman’s rank correlation and binary logistic regression were performed to determine the relationship between CVD risk factors and AsVD.
Results
AsVD was present in 46.3% of KTRs compared to 17.1% of healthy controls (p = 0.004). Left ventricular hypertrophy was present in 92.7% of the KTRs. There were statistically significant differences in waist–hip ratio, systolic blood pressure, mean arterial pressure, urine albumin–creatinine ratio, serum fibrinogen, serum creatinine, estimated glomerular filtration rate, left atrial diameter, left ventricular mass (LVM), and left ventricular mass index (LVMI) between KTRs and controls. A positive relationship was seen between CIMT and certain risk factors for CVD including LVM, LVMI, and mitral valve deceleration time, (p < 0.001). Castelli index 2 and lipoprotein combine index (LCI) showed positive correlation with CIMT. On multivariate analysis, increasing age and kidney transplant status were independent predictors of AsVD after controlling for other risk factors.
Conclusion
AsVD was common among KTRs. Older age and kidney transplant status independently predicted AsVD. Castelli index 2 and LCI correlated with AsVD better than serum lipid parameters.
With current immunosuppression, elevated blood pressure is found in almost 90% of renal graft recipients. Major causes of this are impairment of renal function, secondary to chronic allograft nephropathy or less frequently recurrence of primary renal disease, the use of calcineurin inhibitors as immunosuppressants, uncontrolled renin secretion by the shrunken kidneys of the recipient, stenosing lesions of the transplant artery (or the upstream arteries of the recipient), polycytemia and (genetic predisposition) to hypertension of the graft donor. Even minor degrees of blood pressure elevation have a significant impact on survival of the recipient and on graft survival, presumably by amplifying vascular injury to the graft. In this respect elevation of systolic blood pressure and an abnormal circadian blood pressure profile are of particular relevance. In contrast to previous opinion, ACE inhibitors are indicated in the treatment, but, given the causal role of sodium retention and graft vasoconstriction, diuretics and calcium channel blockers remain mainstays of antihypertensive treatment in the renal allograft recipient.
In this paper the presence of a correlation between plasma Lp(a) levels and periferal vascular disease (PVD) and/or coronary heart desease (CHD) was investigated in 20 dyslipidaemic patients (10 males and 10 females, well matched for age, type of hyperlydaemia and other CVD risk factors). Lp(a) plasma levels, ECG and carotid and femural artheries duplex ultrasonography were performed in all the patients. No difference in plasma Lp(a) levels between patients without and with carotid and femoral artheries stenotic lesions was observed. On the contrary Lp(a) was significantly higher in patients with ECG signs of coronary ischaemic heart deseases than in patients with normal ECG. These observations confirm the importance of Lp(a) as a risk factor for coronary heart desease in dyslipidaemic patients.
Hyperlipidemia is a major risk factor for atherosclerosis and probably contributes to the increased cardiovascular mortality following renal transplantation. We studied the lipid profiles of 62 adults (29 males) with stable renal function (mean plasma creatinine 0.14 mmol/l, SD 0.07), 7 months to 21 years after renal transplantation. Fifteen patients (24%) were above the age- and sex-adjusted 95th percentile for total triglyceride and 10 (16%) for total cholesterol concentrations when compared with a local reference population. The most common lipoprotein abnormalities were type IIa (19%) and type IIb (13%). Multiple regression analysis demonstrated that the use of diuretics and angiotensin-converting enzyme inhibitors were significant factors determining plasma triglyceride concentrations. There were significant bivariate associations between plasma triglyceride concentration and duration since transplantation, plasma creatinine concentration and the use of ciclosporin and diuretics. Duration since transplantation and ciclosporin use were significant factors determining lower plasma cholesterol concentrations. The use of ciclosporin and diuretics was associated with a significantly higher apolipoprotein (apo) B concentration. The cholesterol/HDL cholesterol risk ratio correlated poorly with the apo B/apo A-1 ratio. The value of these ratios as predictors of coronary artery disease need to be established in renal transplant recipients.
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Hyperlipidemia, long recognized as a difficult and common problem following organ transplantation, may be the underlying cause of the accelerated atherosclerosis observed in heart transplant recipients and children with renal transplants. In addition, hyperlipidemia may play a role in late renal graft loss. The cause of post-transplant hyperlipidemia is unclear. In patients treated with azathioprine and prednisone, hypertriglyceridemia is the commonest finding and probably results from an increased consumption of calories from carbohydrate and fat following resolution of uremia, in conjunction with glucose intolerance secondary to steroid administration. In patients treated with cyclosporine, hypercholesterolemia is the most common form of hyperlipidemia. Cyclosporine is a lipophilic drug that is transported in the plasma, largely in association with lipoproteins, and may require the low-density lipoprotein (LDL) receptor for internalization into cells. Hypercholesterolemia may result from interference with the basic cholesterol feedback mechanism via the LDL receptor. In addition, cyclosporine affects bile acid synthesis and worsens glucose tolerance, both factors that may promote hyperlipidemia. The first therapeutic approach to hyperlipidemia in the transplant recipient is dietary calorie-fat restriction and supplementation with soluble fiber. Ongoing clinical trials of the available pharmacologic lipid-lowering agents are addressing the safety and efficacy of these agents in the setting of immunosuppression; until that time, they should be used cautiously and in low doses.
One of the effects attributed to CsA is a possible acceleration of atherogenic processes, which contributes to the failure of transplanted organs. This study was undertaken to evaluate the effect of CsA and two vehicles, cremophor and ethanol, in an experimental model of arterial autograft in the rat. Female Sprague-Dawley rats were distributed into 3 study groups: Group 1 (control) had an arterial autograft in the common iliac artery without pretreatment; group 2 (CsA-cremophor) animals were pretreated with a daily dose of CsA (5 mg/kg, Sandimmun) for 4 days before the autograft was made; and group 3 (CsA-ethanol + Tween) animals were pretreated for 4 days before implantation of the autograft with CsA in a vehicle of ethanol + Tween at the same dose as used in group 2 (5 mg/kg). The study periods were 7, 14, 21, 30, and 50 postoperative days. Studies were made by optical microscopy, transmission electron microscopy, scanning electron microscopy, and autoradiography. Evaluation of the results showed that in the control group the postoperative repair process lead to formation of an intimal neolayer throughout the entire surgical zone, with scant participation of white cells. Group 2 (CsA-cremophor) had a marked increase in luminal thrombogenicity, important adhesion and infiltration of white cells, loss of smooth muscle cells in the medial layer, and atherogenic degeneration of the medial layer. The generation of the neointimal layer is delayed by 2 weeks with respect to the control group. However, once the neointimal begins to form, its thickness increases rapidly, reaching values similar to those seen in the control group at 50 days. The myointima also shows atherogenic characteristics, such as monocyte-macrophage infiltration and dystrophic calcification. In group 3 (CsA-ethanol+Tween, that is, CsA in a nonoleaginous vehicle), the effects were similar to those seen in group 2 (CsA-cremophor), with a reduction in the presence of lipid-laden cells in the medial layer. Based on these observations, we conclude that CsA per se induced atherogenic changes in the repair process of the arterial lesion that were independent of the vehicle of administration. CsA delayed, but did not inhibit, formation of a myointima and the myointima formed exhibited atherogenic characteristics. The most important effects were noted in the medial layer, which experienced intense degeneration.
To assess the influence of long-term hemodialysis on arterial compliance, the elastic vessel wall properties of the common carotid artery were determined in 20 normotensive renal transplant recipients (age 44.7 +/- 4.1 years) 8-12 weeks after first transplantation and in 10 healthy controls (age 45.9 +/- 5.2 years). Arterial distension was measured by using a multigate pulsed Doppler system, blood pressure curve was recorded by finger-plethysmography. 10 patients with a prior long-term hemodialysis of 51 +/- 11 months were compared to 10 patients with a prior short hemodialysis of 18 +/- 7 months. The patients and controls had been matched in respect of age, sex and blood pressure. In the long and short-term hemodialysis group, the proportion of patients (n = 10) with a history of mild hypertension was similar--mild hypertension for 25 +/- 10 months (n = 5) and for 27 +/- 9 months (n = 5). In the group with long-term hemodialysis, the cross-sectional compliance and the distensibility coefficient was significantly reduced in comparison to the group with short-term hemodialysis (p < 0.005) and to the control group (p < 0.001). A significant inverse correlation between the hemodialysis period and the distensibility coefficient (r = -0.59; p < 0.005) showed a decrease in arterial compliance with the length of hemodialysis treatment. The results demonstrate that vessel wall elasticity decreases with the length of hemodialysis treatment and is reduced by hemodialysis-dependent factors, which are detached from sustained arterial hypertension. As cause of reduced arterial compliance in long-term hemodialysis hypervolemia, hypercirculation and disturbed calcium-phosphate metabolism is suggested.(ABSTRACT TRUNCATED AT 250 WORDS)
The initial aim of this study was to evaluate the possibility of influencing atherosclerosis in hyperlipidaemic renal transplant patients by lowering blood lipids with gemfibrozil treatment.
Although this double-blind, randomized trial was stopped after 6 months owing to the suspicion of drug interference, we report here on the results of baseline ultrasonographic examinations.
The outpatient clinic at the Department of Transplantation Surgery, Huddinge University Hospital, Huddinge, Sweden.
The carotid arteries were examined in 16 out of the 19 kidney transplant patients included in the study using an ultrasonographic duplex scanner.
Plaque occurrence and the common carotid intima-media thickness of the renal transplant recipients were compared to the same parameters in a normotensive control group of approximately the same age from a previous study.
An increased prevalence of plaque (75% of the patients having plaque on one or both sides) was seen in the hyperlipidaemic renal transplant patients in comparison with the control group (16%; P < 0.001). The common carotid intima-media complex was thicker (P < 0.05), and the lumen diameter and the calculated cross-sectional intima-media area were greater (P < 0.01-0.001) in the transplant recipients.
Markedly increased atherosclerotic wall changes are seen in the carotid arteries of patients with hyperlipidaemia after renal transplantation.
The optimal target haemoglobin during treatment with recombinant human erythropoietin (r-HuEPO) is still controversial. The
impact of haemoglobin on cardiovascular function or survival, on physical performance and on medical rehabilitation have to
be taken into consideration. Although currently there is no solid evidence to show that haemoglobin beyond that recommended
by the ad hoc committee of the National Kidney Foundation improves survival, sound theoretical arguments can be offered for
this proposition, particularly in cardiac patients. It is sensible to individualize the target haemoglobin and to avoid rapid
correction of anaemia.
Genetic abnormalities in two metabolic steps in homocysteine degradation: transsulfuration and remetylation can cause raised plasma homocysteine concentration. Homocysteine appeared to be an independent arteriosclerotic risk factor in the coronary, cerebral and peripheral circulation and elevated homocysteine levels have been found in chronic renal failure patients undergoing hemodialysis treatment and in transplant patients as well. Homocysteine has a direct toxic effect on endothelial cells, reduces normal activation of protein C by endothelial cells, increases the binding of Lp(a) to plasmin-modified fibrin, induces tissue factor procoagulant activity and inhibits the cofactor activity of thrombomodulin. Treatment with folic acid and piridoxine can lower the high level of homocysteine and should be associated with a clinical benefit.