Key words : Arterial stiffness, Cognitive dysfunction, Renal transplantation

Introduction

Chronic kidney disease (CKD) is a well-established independent risk factor for cardiovascular disease, including coronary artery disease.¹ Patients with end-stage renal disease (ESRD) face a substantially higher risk of cardiovascular events compared with the general population.² Although kidney transplant reduces the risk of fatal and nonfatal cardiovascular events compared with dialysis, kidney transplant recipients still have a higher risk of cardiovascular complications than healthy individuals.^3,4

Atherosclerosis, a key driver of cardiovascular events, leads to remodeling and narrowing of coronary, cerebral, and peripheral arteries.⁵ Arterial stiffness, which develops during the atherosclerotic process, can be measured using pulse wave velocity (PWV). Aortic PWV, measured between the carotid and femoral arteries, serves as a predictor for cardiovascular events. Elevated PWV is associated with higher all-cause and cardiovascular-related mortality.⁶

Cognitive dysfunction is characterized by impair-ments in 1 or more cognitive domain, including learning and memory, language, executive function, complex attention, sensorimotor function, and social cognition. Patients with CKD are at a higher risk of cognitive impairment than the general population.⁷ The prevalence of cognitive impairment increases with disease severity, affecting up to 30% of young and middle-aged patients with stage 5 CKD and as many as 55% of patients aged >75 years.⁸ Patients with stage 5 CKD are at 3-fold higher risk of developing cognitive impairment than healthy individuals.⁹

The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are widely used tools for the evaluation of cognitive function. Both tests have been validated in Turkey and are integral to understanding cognitive function in clinical research.

To the best of our knowledge, no studies have explored the relationship between PWV and cognitive function in kidney transplant recipients. This population is particularly vulnerable to cognitive impairment because of the interplay of CKD-related factors, comorbidities, and the long-term effects of transplantation. In this study, we aimed to investigate the potential association between PWV and cognitive impairment in kidney transplant recipients.

Materials and Methods

Study design and participants
This cross-sectional observational cohort study included 112 kidney transplant recipients who were receiving regular follow-up at a tertiary care nephrology center between January 2015 and March 2021. We compared these patients with a control group of 112 healthy individuals aged 18 years or older, with no history of chronic illnesses. The inclusion criteria for the study group were as follows: patients aged 18 years or older who had undergone kidney transplant at least 6 months prior to enrollment, were not pregnant, and were willing to participate in the study. Exclusion criteria included cerebrovascular disease, hearing or visual impairments, severe psychiatric disorders, severe learning difficulties, or dementia. We also excluded patients who were unable to read and write in Turkish.

Laboratory and clinical measurements
We assessed arterial stiffness by measuring carotid-femoral PWV, using the Atcor Medical SphygmoCor device. We collected demographic and clinical data for kidney transplant recipients, including coexisting chronic diseases and medications, anthropometric measurements, date of kidney transplant, donor status, etiology of kidney disease, and pretransplant dialysis history. We included laboratory results from the most recent hospital visit, including drug levels of cyclosporine, tacrolimus, sirolimus, or everolimus.

Questionnaires
Physicians evaluated cognitive function by using the MMSE and MoCA tests. The MMSE is a widely used test for assessment of cognitive impairment, scored from 30 total points. The test measures various cognitive domains, including orientation (10 points), memory (6 points), attention (5 points), language (8 points), and visuospatial function (1 point).10 In a validation study conducted in Turkey, an MMSE cutoff score of 23 demonstrated high sensitivity and specificity for diagnosis of mild dementia.¹¹ The MoCA test, also scored from 30 total points, is primarily used to assess mild cognitive impairment. The test evaluates delayed word recall (5 points), visuospatial/executive function (7 points), language (6 points), attention (6 points), and orientation (6 points).¹² In another validation study in Turkey, a cutoff score of 21 was established to effectively distinguish healthy individuals from those with mild cognitive impairment.¹³ Therefore, a cutoff score of below 23 was used for the MMSE and below 21 for the MoCA.

Statistical analyses
We used SPSS version 20.0 software for statistical analyses. We assessed data normality by using the Kolmogorov-Smirnov test. We compared continuous variables with the Mann-Whitney U test or inde-pendent sample t-test and analyzed categorical variables with the χ2 test. We evaluated correlations between variables by using Pearson or Spearman correlation tests. We used logistic regression to identify predictors of cognitive impairment. P < .05 was considered statistically significant. We deter-mined the sample size based on Tasmoc and colleagues.14 When we used G*Power 3.1.9.4 program for power analysis, for α = 0.05 and power (1-β) = 0.95, we determined a sample size of 94 participants. Considering the 20% data loss, we needed 112 participants for the study.

This study was approved by the local ethical committee in accordance with the principles of the Declaration of Helsinki (Decision KU GOKAEK-2021/06.31, March 18, 2021). Written informed consent was obtained from patients or their guardians.

Results

Demographic and clinical characteristics of the study group
Median age of kidney transplant recipients was 44 years (interquartile range [IQR], 34.25-52.0), and 57% were men. The median age for healthy controls was 41 years (IQR, 33.25-48.75), and 56% were men. No significant differences were shown between the groups in terms of age, sex distribution, or body mass index (Table 1).

Among kidney transplant recipients, 66% had hypertension and 20% had diabetes mellitus. The antihypertensive drug regimens included renin-angiotensin-aldosterone system inhibitors (36.6%), calcium channel blockers (36.6%), beta-blockers (20.5%), and diuretics (5.4%). Pretransplant dialysis history revealed that 54 patients (45%) underwent hemodialysis and 30 patients (24%) had peritoneal dialysis. Most kidney transplants were from living donors (97%) (Table 2). The etiology of ESRD in this group is shown in Figure 1.

Kidney transplant recipients had a median crea-tinine level of 1.2 mg/dL, hemoglobin of 12.96 g/dL, and corrected calcium of 9.8 mg/dL (Table 3).

Comparison of pulse wave velocity and cognitive function between groups
Pulse wave velocity was significantly higher in the patient group (median 8.6 m/s; IQR, 7.5-9.9; P = .001) compared with healthy controls (median 7.1 m/s; IQR, 6.3-7.7; P < .001), reflecting greater arterial stiffness in the patient group. Cognitive function scores were significantly lower in the patient group. Median MoCA score was 23.5 (IQR, 20-26) in patients and 25 (IQR, 23-27) in controls (P < .001). Similarly, MMSE scores were slightly lower in patients (median 29; IQR, 25-30) than in controls (median 29; IQR, 28-30; P = .001). Cognitive impairment was identified in 14% of patients using MMSE and 31% using MoCA; no people in the control group showed impairment on MMSE, and only 7% scored below normal on MoCA.

Correlation between pulse wave velocity and cognitive function
In the patient group, PWV was negatively correlated with both MMSE (r = -0.25, P = .011) and MoCA (r = -0.24, P = .018) scores, indicating that increased arterial stiffness was associated with poorer cognitive performance (Table 4). Similarly, in the control group, PWV negatively correlated with MMSE (r = -0.279, P = .021) and MoCA (r = -0.369, P = .002) scores.

Relationship between PWV and other parameters in the patient group are presented in Table 5. A strong correlation was observed between MMSE and MoCA scores (r = 0.87, P < .001).

Multivariate analysis of cognitive impairment predictors
Multivariate regression analysis showed that education duration was the strongest predictor of cognitive impairment. The odds ratio (OR) was 0.58 (95% CI, 0.42-0.81; P < 0.001) for MMSE and 0.67 (95% CI, 0.55-0.84, P < .001) for MoCA. PWV was significantly associated with cognitive impairment on MMSE (OR = 2.13; 95% CI, 1.19-3.77; P = .01) but not on MoCA (OR = 0.82; 95% CI, 0.55-1.21; P = .31). Low albumin levels and older age were also significantly associated with MoCA scores (P = .015 and P = .027, respectively) (Table 6).

Discussion

Cardiovascular disease is the leading cause of mortality in kidney transplant recipients, thus emphasizing the importance of assessing and managing cardiovascular risk in this population. Pulse wave velocity is the gold standard for evaluation of arterial stiffness and is strongly associated with cardiovascular and all-cause mortality.^15,16 Studies reported higher PWV in transplant patients compared with healthy individuals but lower than in ESRD patients, which are findings consistent with our study.^17,18

In our study, elevated PWV was significantly associated with markers of inflammation and kidney dysfunction, such as C-reactive protein, urea, proteinuria, and uric acid. These findings underscore the role of inflammation and kidney disease severity in arterial stiffness.¹⁹

Cognitive impairment is an important but unde-rexplored issue in kidney transplant recipients. Although some studies have reported improvements in cognitive function after transplant, particularly in memory, attention, and psychomotor skills,^20,21,22,23 others have reported persistent deficits.^24,25 Some other studies have shown that results of cognitive function tests, such as MOCA and MMSE, were lower in kidney transplant recipients than in healthy individuals.^26,27 Our findings confirmed that cognitive function in transplant recipients, as assessed by MMSE and MoCA, was significantly lower than cognitive function in healthy controls. Furthermore, PWV was independently associated with cognitive decline, particularly with MMSE scores. The relationship between PWV and cognitive impairment may be mediated by cerebrovascular disease. The primary mechanism underlying cognitive impairment in CKD and kidney transplant recipients is thought to be cerebrovascular disease, particularly small vessel disease.²⁸ Cardiovascular risk factors, such as diabetes, hypertension, and dyslipidemia, contribute to both clinical and subclinical cerebrovascular damage. Imaging studies have shown small vessel infarcts and white matter lesions in these patients.^7,29,30 The observed strong negative correlation between PWV and cognitive scores supports this hypothesis.

Interestingly, our multivariate regression analysis revealed that PWV was an independent predictor of cognitive function on MMSE but not MoCA. This discrepancy may reflect differences in the cognitive domains evaluated by each test. The MMSE test primarily measures general cognitive functions, which may be more affected by vascular factors such as arterial stiffness. In contrast, the MoCA test emphasizes executive functions, which are influenced by education and other confounders. These variations highlight the importance of selecting appropriate cognitive tests tailored to the specific clinical and population characteristics.

Other contributors to cognitive impairment may include anemia, inflammation, and metabolic abnor-malities. Posttransplant anemia, hypoalbuminemia, albuminuria, and hypocalcemia have been previously associated with cognitive dysfunction, which are findings that align with our results.^{31,32 33-36}

This study had several limitations. Although we observed a significant association between PWV and cognitive impairment, this relationship reflected correlation rather than causation. Factors such as age, hypertension, diabetes, and immunosuppressive therapy may contribute to both arterial stiffness and cognitive dysfunction, potentially confounding the observed association. In addition, the ultraso-nographic method used to assess arterial stiffness, although practical, is subjective and not a gold standard technique. Future longitudinal studies are needed to validate and further explore these findings.

Conclusions

Cardiovascular disease and cognitive impairment are significant complications in kidney transplant recipients. Elevated PWV is a critical marker of cardiovascular risk and is associated with cognitive impairment. Routine cognitive function tests, such as MMSE and MoCA, alongside cardiovascular evaluations, are essential for early detection of cognitive decline in this population. Our findings underscore the need for regular cardiovascular and cognitive care to improve outcomes for kidney transplant recipients, providing a foundation for future research.

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