Effect of Kidney Transplant Type on Coronary Endothelial Function in Individuals with Chronic Kidney Disease

Introduction

OBJECTIVE:

The aim of this study was to compare coronary vascular endothelial function in patients with cadaver donor transplantation, living donor transplantation, and age-matched healthy controls, and to evaluate the impact of transplant type on echocardiographic parameters and NT-proBNP values. Understanding whether donor type impacts endothelial recovery could inform cardiovascular risk stratification and guide post-transplant monitoring protocols.

Material and Methods

PATIENTS:

The project was approved by the institutional review board of Medicana International Hospital (19.04.007). All participants provided written informed consent. The study protocol adhered to good medical and laboratory practice and the recommendations of the Declaration of Helsinki on Biomedical Research involving Human Subjects. This prospective observational study was conducted between September 2016 and March 2023. As this was a prospective observational study, no randomization was performed. However, the cardiologists performing and analyzing the CFVR and echocardiographic measurements were blinded to the patients’ group allocation (LDT, CDT, or control) to minimize observer bias. During this period, a total of 91 patients underwent renal transplantation (60 living donor transplantation and 31 cadaver donor transplantation) at Medicana International Hospital. The study included patients who underwent living donor transplantation (Group LDT, 50 out of 60) and cadaver donor transplantation (Group CDT, 25 out of 31).

Additionally, 25 healthy subjects of similar age, sex, and body mass index (BMI) were included as controls. Patients eligible for inclusion were enrolled in the renal transplant program and were between the ages of 35 and 65 years. Exclusion criteria included valvular heart disease, prior coronary interventions, congestive heart failure, and graft failures. Patients with inadequate visualization of the left anterior descending coronary artery using Doppler echocardiography were also excluded. Inadequate visualization was defined as the inability to obtain a clear and continuous color Doppler signal from the mid-to-distal LAD segment, with a well-defined spectral envelope during both baseline and hyperemic phases. In the LDT group, 10 patients were excluded (graft failure, n=2; prior coronary intervention, n=3; valvular heart disease, n=2; congestive heart failure, n=2; inadequate LAD visualization, n=1), resulting in 50 patients included in the analysis. In the CDT group, 6 patients were excluded (graft failure, n=1; prior coronary intervention, n=2; congestive heart failure, n=1; inadequate LAD visualization, n=2), leaving 25 patients for analysis. The healthy control group consisted of 25 volunteers with no known cardiovascular or renal disease. A flow diagram summarizing patient inclusion and exclusion is provided in Figure 1. A review of medical records including age, sex, BMI, smoking status, duration of CKD, duration of HD treatment, and comorbidities was undertaken. Hemoglobin (Hbg), platelet (Plt) and white blood cell count (WBC), C-reactive protein (CRP), blood glucose, serum creatinine, triglyceride, low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) values of the participants were measured within 1 week before kidney transplantation. Blood samples for biochemical analysis were drawn between 08: 00 and 09: 00 am. Baseline systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and heart rate (HR) were recorded for all participants.

All patients and controls underwent Doppler echocardiography assessment to evaluate coronary endothelial function. Coronary flow velocity reserve measurements were taken at baseline (within one week before kidney transplantation – CFVR-1) and at 6 months after transplantation (CFVR-2). Healthy subjects underwent a single CFVR measurement as a control group. Groups were compared in terms of measured CFVR values. Changes in CFVR value after kidney transplantation were also evaluated in Group LDT and Group CDT. During Doppler echocardiography procedures, left ventricular ejection fraction (LV-EF1/LV-EF2), left ventricular end-diastolic diameter (LVED-D1/LVED-D2), and left ventricular end-systolic diameter (LVES-D1/LVES-D2) were measured for all patients with CKD. Simultaneously, the plasma concentration of N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP-1/NT-proBNP-2) was measured in patients who underwent kidney transplantation. The groups were compared based on these parameters. Group LDT and Group CDT were also compared regarding the percentage of patients with an LV-EF increase of more than 10% after kidney transplantation. Correlations between age, BMI, duration of CKD or HD treatment, and CFVR were assessed. The impact of sex, smoking status, and the presence of diabetes mellitus (DM), hypertension (HT), CAD, and chronic obstructive pulmonary disease (COPD) on CFVR was also investigated.

CORONARY FLOW VELOCITY RESERVE ASSESSMENT:

All CFVR measurements were performed using a Vivid 7 echocardiography device (General Electric, USA), which was calibrated regularly according to the manufacturer’s instructions. The consumption of stimulants such as alcohol and caffeine was halted 24 hours before CFVR measurement. Studies were conducted in a quiet, temperature-controlled room (23–25°C) with participants in a supine position.

Coronary flow velocity reserve measurements were performed using the Vivid 7 echocardiography device (General Electric, USA) with a middle-range-frequency (3–8 MHz) broadband transducer in the left anterior descending (LAD) coronary artery via transthoracic color Doppler echocardiography. The coronary blood in the mid-to-distal LAD coronary artery was examined by color Doppler flow mapping guidance with the optimal velocity range (+12 to +15 cm/s). Then, the sample volume (1.5 or 2.0 mm wide) was positioned on the color signal in the LAD coronary artery. Variables of the LAD coronary artery velocity were measured using the fast Fourier transformation analysis. After baseline recordings of flows, dipyridamole (0.56 mg/kg; Persantine, Boehringer Ingelheim) was administered over 4 minutes. An additional infusion of dipyridamole (0.28 mg/kg over 2 minutes) was used unless the heart rate was a 10% increase from the baseline. Two minutes after the end of the infusion, hyperemic spectral profiles in the LAD coronary artery were recorded. All images were recorded for playback analysis and were later measured off-line. Average diastolic peak flow velocity (ADPV) was measured at baseline (ADPVB) and under hyperemic conditions (ADPVH). The coronary flow velocity reserve was defined as the ratio of ADPVH to ADPVB. A CFVR value <2.0 was considered abnormal [18,19]. The cardiologists performing and analyzing the CFVR and echocardiographic measurements were blinded to the patient’s group (LDT vs CDT vs HC) to eliminate observer bias.

PRIMARY AND SECONDARY OUTCOMES:

The primary outcome was to assess the impact of kidney transplant type on ED using CFVR measurements in CKD patients. Therefore, we compared CFVR values before and after kidney transplantation between Group LDT and Group CDT. We also compared the increase in CFVR values of the groups after kidney transplantation. Secondary outcomes were the LV-EF, LVED-D, LVES-D, and NT-proBNP values compared between groups. Furthermore, Group LDT and Group CDT were compared in terms of the percentage of patients with an LV-EF increase exceeding 10% after kidney transplantation. Moreover, we analyzed the correlation between CFVR and age, BMI, duration of CKD, or duration of HD treatment.

DATA COLLECTION PROCESS:

Exposure data (donor type, CKD and HD duration, comorbidities) were obtained from hospital medical records, while outcome data (CFVR, LV function, NT-proBNP) were measured prospectively during study visits. All transplanted patients were followed for 6 months after surgery, during which the second CFVR and echocardiographic measurements were obtained. All echocardiographic and CFVR measurements were performed by 2 cardiologists, each with more than 10 years of experience in echocardiography and coronary flow assessment, using a standardized protocol to minimize inter-observer variability. Measurements were obtained in the morning, after at least 10 minutes of rest in the supine position, using a high-resolution Doppler echocardiography system (Vivid E9, GE Healthcare, USA) with a 7–12 MHz transducer. For each patient, 3 consecutive measurements were recorded, and the mean value was used for analysis. Biochemical parameters, including CRP and NT-proBNP, were obtained from fasting blood samples collected within 1 week before and 6 months after transplantation. Data were recorded in an electronic case report form, and completeness and accuracy were verified by an independent investigator not involved in patient care.

STATISTICAL ANALYSIS:

A priori power analysis was performed using GPower version 3.1.9.7 (Heinrich Heine University, Düsseldorf, Germany) to determine the required sample size. Based on previous studies evaluating changes in coronary flow velocity reserve (CFVR) before and after kidney transplantation, we anticipated a mean difference of 0.4 in CFVR values with a standard deviation of 0.7. To detect this difference with 80% power and a two-sided alpha of 0.05, a minimum of 34 participants per transplant group was required. To account for potential dropouts or incomplete data, we aimed to include at least 40 patients in each transplant group [20].

All statistical analyses were performed on GraphPad Prism Software v7 (La Jolla, California, USA). Data are presented as mean ± standard deviation (SD), medians (interquartile range), and n numbers with percentages, as appropriate. The Shapiro-Wilk test was used to check whether the data fit a normal distribution. For normally distributed data, pairwise comparisons were performed using the independent Student’s t test, and multiple comparisons were performed using the one-way analysis of variance (ANOVA) test. Non-normally distributed data were analyzed using the Kruskal-Wallis (with Dunn’s multiple post hoc test) and Mann-Whitney U tests for multiple variables and 2 data sets, respectively. The chi-square test was performed for categorical variables. The strength of the relationship between the 2 variables was tested using the Spearman’s correlation (r values for correlation: 0.20–0.39 for “weak”, 0.40–0.59 for “moderate”, 0.60–0.79 for “strong” and 0.80–1.0 for “very strong”). The value of P<0.05 was considered statistically significant. There were no missing data for the variables analyzed. For multiple comparisons, P values were adjusted using the Bonferroni correction method.

Results

BASELINE CHARACTERISTICS:

A total of 116 participants (60 in Group LDT, 31 in Group CDT, and 25 in Group HC) were initially recruited; 100 participants completed the study (50 in Group LDT, 25 in Group CDT, and 25 in Group HC) (Figure 1). The groups were comparable in age, sex, BMI, and smoking status (Table 1). The duration of CKD and hemodialysis was significantly longer in Group CDT compared to Group LDT (P=0.0031 and P=0.0011, respectively).

HEMODYNAMIC PARAMETERS:

Mean systolic arterial pressure (SAP) was higher in Group CDT than in both Group LDT and Group HC (P=0.0244 and P=0.0012, respectively), while diastolic arterial pressure (DAP) and heart rate (HR) were similar among groups (P=0.8592 and P=0.6394, respectively).

LABORATORY FINDINGS:

Hemoglobin levels were highest in Group HC (P<0.0001 vs Group LDT; P=0.0001 vs Group CDT). CRP and fasting glucose were significantly higher in Group CDT compared to Group HC (P=0.0425 and P=0.0460, respectively). Serum creatinine was lower in Group HC than in both transplant groups (P<0.0001 for all) (Table 2).

CORONARY FLOW VELOCITY RESERVE (CFVR) OUTCOMES:

Baseline CFVR (CFVR-1) was higher in Group HC compared to both transplant groups (p<0.0001 for all) (Table 3). CFVR-1 was similar between Group LDT and Group CDT (P=0.1904). Post-transplant CFVR (CFVR-2) was not significantly different between the transplant groups (P=0.6727).

Both transplant groups demonstrated significant CFVR improvement after transplantation (LDT: P=0.0011; CDT: P=0.0002), but post-transplant CFVR values remained lower than those in healthy controls (HC vs LDT: P=0.0002; HC vs CDT: P=0.0051). The absolute CFVR increase was greater in Group CDT than in Group LDT (0.19±0.13 vs 0.11±0.13, P=0.0019).

The proportion of patients with CFVR <2 at baseline differed between the transplant groups (P=0.045), but post-transplant proportions were similar (P=0.3108).

ECHOCARDIOGRAPHIC OUTCOMES:

Baseline LV-EF and 6-month post-transplant LV-EF were similar between transplant groups (P=0.9621 and P=0.3882). Both groups showed significant LV-EF improvement after transplant (LDT: P=0.0412; CDT: P=0.0471), with 36% of patients in each group achieving ≥10% EF increase (P>0.9999) (Table 4).

Baseline LVED-D, LVES-D, and LVED-D2 were similar between groups. LVES-D2 was lower in Group CDT than in Group LDT (P=0.0116). LVED-D and LVES-D decreased significantly in Group LDT, while in Group CDT only LVES-D decreased significantly (Table 4).

BIOMARKER CHANGES (NT-PROBNP):

Baseline NT-proBNP was higher in Group LDT than in Group CDT (P=0.0132). Six months after transplant, NT-proBNP levels were similar (P=0.8342) and showed significant reductions in both groups (P<0.0001 for all) (Table 4).

CORRELATION ANALYSES:

CFVR-1 correlated negatively with age, hemodialysis duration, and CRP (r=−0.2698, P=0.0193; r=−0.3856, P=0.0006; r=−0.3652, P=0.0013) (Figure 2). No significant relationships were found between CFVR and sex, smoking, diabetes, hypertension, coronary artery disease, or chronic obstructive pulmonary disease.

Discussion

This study on the effect of kidney transplant type on the coronary endothelial function of patients with CKD has yielded 5 key findings. Firstly, individuals with CKD had lower CFVR values compared to healthy counterparts. Secondly, CFVR values measured before and after kidney transplantation were similar between Group LDT and Group CDT. However, the number of patients with a CFVR value measured before transplantation less than 2 was higher in Group CDT. Thirdly, a notable increase in CFVR values was observed after transplantation in both groups, with a more pronounced increase following cadaver donor transplantation. Fourthly, CFVR values were inversely correlated with patient age, hemodialysis duration, and CRP levels. Lastly, there was a statistically significant increase in LV-EF after kidney transplantation in Group LDT and Group CDT. The number of patients with a 10% increase in LV-EF value after kidney transplantation was 36% in both groups. In addition, there was a significant decrease in NT-proBNP value 6 months after transplantation.

Patients with moderate to severe CKD face a heightened risk of cardiovascular events compared to those with mild renal failure and the general population [21,22]. For young individuals with severe CKD, the annual mortality risk is approximately 1000 times higher than that of age-matched individuals with healthy renal function, underscoring the substantial cardiovascular burden in kidney disease [22]. Endothelial dysfunction is a major contributor to this elevated cardiovascular risk in CKD patients. Numerous studies have demonstrated impaired endothelium-dependent vasodilation in CKD patients, which worsens with increasing disease severity [23,24]. In terms of functional responses of the peripheral microvasculature as evaluated by flow-mediated dilation (FMD), numerous studies have also shown that CKD patients have a significant deficiency in endothelium-dependent vasodilation [24–28], which increases with increasing CKD severity [28,29]. In the current study, we used CFVR measurement to evaluate ED, because CFVR is a novel physiologic imaging biomarker that complements both anatomic and semiquantitative perfusion assessments of coronary ED and CVD severity [30,31]. We observed lower CFVR values in the patients with CKD, reiterating the presence of impaired endothelium-dependent dilatation in renal failure [10,24,32].

Previous studies have found abnormal endothelial function in patients undergoing HD and post-renal transplantation [33–35], with some studies reporting that endothelial function is more impaired in hemodialysis patients than in renal transplant recipients [34,35]. Moreover, inflammation has been shown to enhance cardiovascular risk and mortality in hemodialysis patients, with elevated C-reactive protein (CRP) levels emerging as a possible mechanistic link [36,37]. A study investigating the relationship between ED, atherosclerosis, and inflammation in CKD patients has shown that abnormal endothelial function persists across all stages of CKD, including pre-dialysis, dialysis, and post-transplantation [24]. Consistent with these findings, our study observed an increase in CFVR values after transplantation in CKD patients, although these values did not reach levels seen in the healthy population. This suggests that ED persists in CKD patients even after kidney transplantation, indicating an ongoing risk of CAD. Notably, the increase in CFVR values was more pronounced following cadaver donor transplantation, potentially linked to the slightly lower baseline CFVR values in the CDT group. This difference may also reflect underlying biological mechanisms, such as prolonged exposure to uremic toxins, more severe microvascular remodeling, and increased arterial stiffness in patients who wait longer for cadaveric organs. Indeed, Salib et al reported that elevated fibrosis biomarkers and increased arterial stiffness 2 years after transplant were associated with higher cardiovascular morbidity and mortality in kidney transplant recipients, supporting the notion that vascular dysfunction may persist long-term despite successful transplantation [38]. Additionally, differences in ischemia–reperfusion injury, immune activation, and inflammatory milieu between living and cadaveric grafts could contribute to variations in endothelial recovery. Future mechanistic studies assessing biomarkers of endothelial injury, oxidative stress, and vascular stiffness may help clarify these pathways.

Atherosclerosis and cardiomyopathy are commonly observed in patients with CKD [24,25]. Renal transplantation is known to improve left ventricular hypertrophy and systolic dysfunction [39]. Since the 1980s, several studies have reported that renal transplant reduces left ventricular hypertrophy and enhances LV-EF independently of changes in blood pressure, hematocrit, or volume status [40–42]. It has also been noted that echocardiographic parameters improve following kidney transplantation [43]. Bialostozky et al demonstrated that the percentage of patients with normal LV-EF doubled after transplantation, with a mean increase of approximately 10% in post-procedure LV-EF [39].

In the current study, we observed an approximate 7% increase in LV-EF in post-transplant patients. Furthermore, the percentage of patients with a 10% increase in EF after kidney transplantation was 36% in both groups. Left ventricular hypertrophy is present in 80% of CKD patients and is associated with both hemodynamic and metabolic stress. Chronic volume and pressure overload lead to concentric hypertrophy and LV dilatation [44]. Our echocardiographic evaluation revealed that in Group LDT, LVED-D, LVES-D, and NT-proBNP values decreased after transplantation. However, in Group CDT, while LVES-D and NT-proBNP values decreased, LVED-D values did not change after the procedure. This observation may be linked to the longer duration of renal failure in patients undergoing cadaver donor transplantation and their prolonged exposure to chronic volume overload. According to our findings, patients in Group CDT had higher SAP values, which could explain the lack of decreased LVED-D post-kidney transplantation.

Our observations are supported by the recent literature. Prabhahar et al (2025) noted that although endothelial function undergoes immediate improvement after kidney transplant, it is only partially restored, and transplant recipients continue to face significant cardiovascular risks due to both transplant-related and traditional factors [45]. Similarly, a recent comprehensive review by Wang et al (2025) showed how persistent factors such as inflammation, oxidative stress, and residual uremic toxins contribute to ongoing endothelial dysfunction in CKD and post-transplant patients [46]. Moreover, Lo Cicero et al (2025) emphasized that uremia-driven endothelial injury and increased arterial stiffness are key drivers of cardiovascular events in CKD, linking chronic inflammation to heightened risks of myocardial infarction and stroke [47]. These insights show that while kidney transplantation mitigates the uremic milieu, additional measures are needed to protect the vasculature. Taken together, our study and these recent findings suggest that kidney transplant recipients should be recognized as a high-risk cardiovascular group in which adjunctive therapies and vigilant cardiovascular surveillance may be warranted to address the persistent endothelial dysfunction.

The primary limitation of this study is the limited number of patients who underwent cadaver donor transplantation. Secondly, the relatively short follow-up duration focused on the early improvement in ED after kidney transplantation, rather than the long-term progression of ED. Thirdly, the presence of comorbidities (eg, diabetes, hypertension, CAD, which were similar between the LDT and CDT groups) makes it challenging to isolate the specific contribution of these factors. Finally, since not all patients underwent coronary angiography, comparisons between groups regarding the presence of CAD could not be made. We did not specifically analyze differences in immunosuppressive therapy or donor organ quality between groups; these factors could also influence cardiovascular outcomes and merit investigation in future studies.

Longer-term studies are needed to determine if the improvements in endothelial function are sustained beyond 6 months and whether additional interventions (eg, aggressive risk factor control or novel therapies targeting endothelial health) can further normalize CFVR in transplant recipients.

Conclusions

In conclusion, kidney transplantation improves endothelial dysfunction and left ventricular systolic function in CKD patients, regardless of whether the donor is living or cadaveric. However, normal CFVR values are not achieved after transplantation, suggesting that cardiac risk factors are not entirely reversed. These patients should be considered a persistent high cardiovascular risk group, warranting ongoing risk factor control and regular vascular function monitoring. Larger, multicenter studies with longer follow-up are needed to confirm whether early post-transplant improvements in CFVR translate into reduced cardiovascular events, and to explore targeted interventions – such as anti-inflammatory or anti-oxidative therapies – to further restore endothelial function.