Background
Patients with chronic kidney disease (CKD) have a higher burden of cardiovascular disease (CVD), including kidney transplant recipients [
1]. Although cardiovascular risk factors improve in the immediate perioperative period, the long-term risk remains high [
2,
3]. CVD is the commonest cause of death in transplant patients with a surviving graft, more so than infection or malignancy [
4].
Endothelial dysfunction, arterial stiffness, and accelerated atherosclerosis are common in stable kidney transplant patients and may contribute to the high cardiovascular event rate [
3,
5,
6]. Endothelial dysfunction, a prerequisite to atherosclerosis, encompasses numerous maladaptive alterations adversely affecting vascular tone, haemostasis, and inflammatory processes within the arterial wall [
7]. Both traditional and non-traditional risk factors in transplant patients can induce endothelial dysfunction [
3,
8]. Calcification of the arterial wall is common in transplant patients and contributes to vascular stiffness [
3,
9].
The nature of the changes in these vascular abnormalities in kidney transplant recipients is unknown. Previous studies mostly examined changes in the vascular properties of transplant patients pre-transplantation and immediately post-transplantation. They were not examined in stable transplant recipients long after transplantation. If these changes are adverse, they may be the result of novel risk factors post-transplantation and may be a cause of the high cardiovascular event rate. This pilot study investigated the changes in endothelial dysfunction, arterial stiffness, and atherosclerosis in stable kidney transplant recipients long into the post-transplant period.
Discussion
This study shows the worsening of vascular structure and function in stable kidney transplant patients, where FMD decreased while cf-PWV and CCA-IMT increased. Change in eGFR was not associated with changes in FMD, CCA-IMT, or cf-PWV. Traditional risk factors including age, BMI, WHR, gender, DM, SBP, and DBP did not correlate with the changes seen. Baseline haemoglobin, corrected calcium, and transferrin was associated with changes in FMD. Baseline transferrin was associated with changes in cf-PWV while baseline phosphate was associated with changes in CCA-IMT.
CKD patients exhibit endothelial dysfunction as measured by FMD [
3,
5]. In previous studies, transplantation has been shown to improve FMD, acutely and at 12 months [
14,
15]. This recovery may be due to improvements in traditional and uraemia-related non-traditional risk factors [
6]. Despite this, FMD values were often still lower compared to controls [
5,
6].
CKD patients demonstrate accelerated atherosclerosis as evidenced by high CCA-IMT [
3,
6]. The impact of renal transplantation on CCA-IMT is conflicting. One study demonstrated CCA-IMT to progressively increase after 2, 4, and 6 months post-transplantation [
16]. Another reported improvements 6 months after transplant [
17]. Despite this, values are often still higher compared to the general population [
3,
17].
Cf-PWV is a marker of arterial stiffness and predicts the appearance of CVD in CKD, including in transplant patients [
11,
18,
19]. Studies evaluating the progression of arterial stiffness over time is conflicting in transplant patients. One study reported no significant change at 12 months after transplantation, while another reported an improvement [
19,
20]. Bachelet-Rousseau’s group compared cf-PWV progression in transplant waitlisted patients who were eventually transplanted or were still transplant-pending. No difference in cf-PWV was observed at baseline and upon 1-year follow-up with a short median time of 6.3 (3.8–10.1) months post-transplantation [
21]. In contrast, Strozecki’s group showed cf-PWV to progress in transplant patients who were enrolled much later at 36 ± 27 months post-transplantation [
22].
Most studies evaluating changes in FMD, CCA-IMT, and cf-PWV in transplant patients do so in immediately post-transplanted subjects. Improvements or non-progression in these parameters shortly after transplantation does not exclude a reversal in recovery. Unlike these studies, our patients were recruited long into the post-transplant period at a median of 86 months post-transplantation. Different pathophysiological mechanisms exist in the development of endothelial dysfunction, accelerated atherosclerosis, and arterial stiffness. Successful kidney transplantation can eliminate important factors that contribute to the progression of these vascular aberrations. However, during long-term follow-up, cardiovascular risk factors often remain and some even worsen, which may explain the progression seen. Additionally, immunosuppression may prevent further improvement and eventual deterioration.
Failure in graft function can explain the progression of endothelial dysfunction in the late post-transplant period. Elimination of ureamic milieu may be particularly important in the restoration of vascular structure and function immediately after transplantation. Interestingly, we found baseline corrected calcium to be associated with changes in FMD and baseline phosphate to be associated with changes in CCA-IMT. Studies have described progressively decreasing FMD with greater renal impairment [
3,
5]. Improvements in eGFR after transplantation can explain improvements in FMD in the newly transplanted. However, continued functional decline after kidney transplantation has been noted, studies have reported rates of graft function loss ranging from − 1.90 mL/min/y to − 2.38 mL/min/y in transplant recipients [
23‐
25]. Indeed, our transplant patients demonstrated worsening kidney function at their follow-up visit. However, we could not demonstrate an association between the decline in eGFR and FMD upon follow-up. We too did not demonstrate an association between changes in cf-PWV and eGFR. However, in contrast, associations between PWV and eGFR are inconclusive [
26,
27]. eGFR has also been shown to be a significant independent predictor of CCA-IMT [
28]. Hence, the restoration in eGFR post-transplant can explain improvements in CCA-IMT. In a study by Yilmaz et al., the improvement in CCA-IMT in their cohort of 178 newly transplanted patients was associated with an accompanying increase in eGFR [
17]. Nevertheless, the decline in graft function thereafter can also explain the inevitable progression of CCA-IMT. Yet, again, although we observed parallel changes in eGFR and CCA-IMT in our transplant patients, we did not demonstrate an association between the two. However, consider that the mean eGFR increased from 6.3 ± 4.0 mL/min/1.73 m
2 to 85.8 ± 13.7 mL/min/1.73 m
2 in patients from Yilmaz’ group [
17]. Whereas we only observed a decrease of 6.06 ± 9.60 mL/min/1.73 m
2 upon follow-up. Correlations between CCA-IMT and eGFR may only be seen with substantial changes in eGFR.
It is important to consider the role of immunosuppressants in enabling the progression seen. Calcineurin inhibitors increase endothelin levels and abrogate nitric oxide-induced vasodilation, making them potent vasoconstrictors [
29,
30]. Additionally, they promote intravascular fibrosis and cause sodium retention leading to hypertension [
30]. Hence, these unwanted effects from immunosuppressants may impair endothelial function and promote arterial stiffness in the long run [
5,
6].
Another factor that warrants consideration is the dyslipidaemia seen in our transplant patients. Metabolic syndrome is a novel multiplex CVD risk factor that includes dyslipidaemia, central obesity, dysglycaemia, and hypertension. It is common in those with CKD, evidenced by reports of prevalence ranging from 30% in stage 3–4 CKD to 69% in incident haemodialysis patients [
31,
32]. Our transplant population had more dyslipidaemics compared to controls. In a cohort of 198 CKD patients, CCA-IMT was found to be closely associated with traditional cardiovascular risk factors, including dyslipidaemia and DM [
33].
Anaemia is common in CKD and its aetiology is multifactorial in nature. However, erythropoietin deficiency seems to be the major factor for explaining low haemoglobin in CKD patients. We found that baseline haemoglobin predicted change in FMD in our transplant patients, while baseline transferrin predicted change in FMD and cf-PWV. Indeed, previously it has been reported that haemoglobin is inversely related to FMD in CKD patients with or without diabetes [
34,
35]. In contrast, the specific effect of transferrin on PWV and FMD in CKD or kidney transplant patients has not been extensively investigated in the literature.
Ultimately, our study had a small sample size, hence it was difficult to reveal correlations between traditional and non-traditional risk factors with the changes observed, including uraemia, and aspects of metabolic syndrome.
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