Association of Coronary Calcium Score on Cardiac PET During Pre-Kidney Transplant Assessment with Persistent Hyperparathyroidism: A Retrospective Study

Introduction

Vascular calcifications are common in chronic kidney disease (CKD) and are associated with increased morbidity and mortality [1]. Patients on dialysis have 2- to 5-fold more coronary calcification than age-matched individuals with angiographically proven coronary artery disease (CAD) [2]. Several mechanisms can adversely affect vascular calcification in CKD, including altered PTH secretion, use of calcium-based binders, and excessive vitamin D therapy [3]. These changes induce vascular smooth muscle cells to change into a chondrocyte- or osteoblast-like cell [4,5], leading to calcifications into the coronaries, peripheral artery, and cardiac valves [4,6]. Furthermore, proteins such as α-Klotho, fibroblast growth factor (FGF)-23, and fetuin A play a critical role in vascular calcification in CKD. In CKD, disrupted phosphate metabolism due to impaired kidney function leads to elevated FGF23 levels, which can promote vascular calcification [7]. α-Klotho, often reduced in CKD, exacerbates this by failing to effectively regulate FGF23 and phosphate levels [8]. Fetuin A acts as a systemic inhibitor of calcification, but its deficiency in CKD contributes to enhanced vascular calcification [9]. Depositions can be either intimal or medial, and show a progressive tendency [4,10,11] The progression of coronary calcifications slows but does not completely halt after kidney transplant (KT), and a higher baseline CCS is associated with a higher risk of progression [12]. CCS provides additional prognostic indicator beyond traditional CV risk factors [1,13,14].

Secondary hyperparathyroidism is also a common complication of CKD. Parathyroid hormone (PTH) levels increase early as kidney function starts to decline until patients reach end-stage kidney disease. After KT, PTH levels decline in most patients [15]. However, only 23% of patients will reach PTH levels within normal range. Furthermore, 20–50% of patients will have persistently elevated PTH values 2 times higher than the normal levels at 12 months after KT, also known as persistent hyperparathyroidism (pHPT) [16–18]. pHPT is typically defined as persistently elevated PTH over 2 times above the upper normal limit in a renal graft that is functioning well (eGFR ≥30 ml/min) during the first 6–12 months after KT [12,19]. High calcium phosphate product, older age, and dialysis vintage before KT are associated with an increased risk of pHPT [15,20]. A significant improvement in secondary hyperparathyroidism (HPT) after KT favorably affects the progression of CCS [12].

There are only limited data on the relationship between CCS and HPT in KTRs [11,21]. Although a significant improvement in secondary HPT after KT favorably affects the progression of CAC [12], the relationship between pHPT and CCS, to the best of our knowledge, has not been studied. In this study we examined the association between CCS, and PTH changes after KT, and more specifically pHPT, at our center. We hope this study helps shed light on the relationship between CCS and pHPT.

Material and Methods

STATISTICAL ANALYSIS:

We used SPSS 26 (IBM, Armonk, NY, United States) for the analysis. Categorical variables were presented as frequencies and percentages and compared using the chi-squared or Fisher’s exact tests, as appropriate. Continuous variables were presented as mean±SD. The Shapiro-Wilk test was used to assess the normality of continuous variables and guide the selection of parametric or nonparametric tests for the comparison of variables. The variables were compared using Welch’s t-test, Student t-test, and Mann-Whitney-U test. Spearman’s rank correlation was applied to evaluate the association between PTH values and calcium score. All clinically relevant independent variables from univariate logistic regression analysis were included in a multivariate logistic regression model to examine the association between risk factors and study outcome. All reported values are two-sided and a P value <0.05 indicated statistical significance.

Results

A total of 111 KTRs were included (Table 1). The average age was 50.4±13 years, 62.2% were men, and 77.5% were living-donor KTRs. Preemptive KT was performed in 7.2%. The dialysis modality used pre-KT was peritoneal dialysis (PD) in 9.9% and hemodialysis (HD) in 82.9% (using an arteriovenous fistula in 41.5% and tunneled hemodialysis catheter in 58.5%). Dialysis vintage (the time on dialysis) was 3±3 years (4.8±3.3 years for deceased donor KT vs 2.4±2.6 years for living-donor KT).

Mean PTH at baseline (before KT) was 64.1±57 pmol/L, 32.7±36.4 pmol/L at 1–6 months after KT, 27.6±26.1 pmol/L at 6–12 months, and 26.2±32.5 pmol/L at 12–24 months. Accordingly, PTH declined significantly from baseline to 12 months by −45.2±53.6 pmol/L (Figure 1). The prevalence of pHPT was 24.3% (n=27).

The mean dialysis vintage was significantly higher in the pHPT group (4±3.2 years) than in the non-persistent group (2.7±2.7years) (P=0.032). DM was less common in patients with pHPT (n=11/27; 40.7%) vs the non-pHPT group (n=56/84; 66.7%) (P=0.023). None of the patients who underwent preemptive KT had pHPT (P=0.195).

Other factors, such as patient demographics, baseline cardiovascular risk factors, types of kidney replacement therapy, types of KT, and metabolic and cardiovascular changes after KT were not significantly different between the 2 groups (Table 2). Additionally, calcium did not significantly change from baseline to 12–24 months after KT in either group, whereas phosphorous dropped significantly in both groups after KT (P=0.006 in non-pHPT and P=0.038 in pHPT); however, the reduction in levels was similar between the 2 groups (P=0.392). Table 2 highlights the differences in calcium, phosphorous and PTH changes among non-pHPT vs pHPT groups.

Severe CCS (≥400) was also significantly more prevalent in the pHPT than the non-persistent group (37% vs 14.3%, P=0.014). However, the findings of the cardiac nuclear stress test and coronary angiogram were not different between the 2 groups. Table 3 highlights the findings of pre-transplant cardiac in non-pHPT groups vs pHPT.

The prevelence of CCS > 400 was sigificatly higher in the pHPT group (37% vs 14.3%, P=0.014); but individual PTH values at baseline (before transplant), 1–6 months, 6–12 months, and 12–24 months after KT were not significantly different between the 2 CCS groups (Table 4).

Additionaly, CCS was positively correlated with PTH change in the patient population (coefficient 0.288, P=0.020), which indicates less improvement of PTH values after KT in those with worse CCS. There were no significant correlations between CCS and PTH values at baseline, 1–6 months, 6–12 months, and 12–24 months.

Multivariate analysis revealed a strong association between pHPT and severe coronary calcifications (CCS >400) (aOR=18.804, P=0.012) but there was not association between pHPT and less severe CCS (Table 5).

Discussion

The present study examined the association of pHPT in KTRs with a variety of patient demographic and clinical variables, including several components of pre-KT cardiac assessment, such as CCS. Of the 111 KTRs, pHPT was evident in 24.3% of patients and high CCS (>400 Agatston units) was present in 19.8%.

Studies have reported a variable prevalence of pHPT based on the definition used, recipient age, dialysis vintage, rate of pre-emptive KTs, pre-transplant PTH levels, and rate of calcimimetics use [29–31]. Consistent with previous studies [29,31], our study showed that patients in the pHPT group had significantly longer dialysis vintage [30,32].

The prevalence of high CCS (CCS >400 Agatston units) in the present study is similar to that of previous reports, which reach 33% [33,34]. Older age, male sex, diabetes, and longer dialysis vintage have been linked to higher CCS in ESKD [11]. However, the relationship between coronary calcifications and secondary hyperparathyroidism after KT is less clear. Two previous studies [6,11] have found no association between CCS and pre-KT PTH values; however, Megahed et al [21] reported a possible association. To the best of our knowledge, this is the first study to examine the relationship between CCS and PTH values after KT.

The relationship between serum calcium and phosphorus with CCS has also been reported inconsistently [4,6,11,21]. Our study showed no association between CCS and isolated pre- and post-KT PTH values, but there was a strong association between severe CCS and pHPT. Additionally, the current study showed that a significant improvement in secondary HPT after KT was favorably correlated with lower baseline CCS. These findings are in line with the findings of Cianciolo et al, who showed that a significant improvement in secondary HPT after KT significantly reduces the progression of coronary calcifications after KT [12].

CCS is associated with a stepwise increase in cardiac events among the general population. However, many studies have suggested that only severe CCS is involved in this relationship [27,28]. In KT candidates, CCS ≥400 provides a sensitivity of 70% for diagnosing obstructive CAD in a proximal segment [28]. The same CCS threshold is also associated with increased risk of CV disease and all-cause mortality in CKD patients [35]. Our study also suggests a similar threshold governing the relationship between CCS and pHPT.

The finding of strong relationships between CCS and pHPT but the lack of such relation with isolated PTH values is also very intriguing. It is possible that severe CCS is a consequence of worse metabolic and inflammatory background before KT, leading to higher rate of pHPT [36–38]. On the other hand, studies have reported that arterial calcifications develop at a different rate in dialysis patients, despite similar exposure to these risk factors and regardless of the dialysis vintage [4]. Studies have also suggested the presence of protective factors in blood vessels and in the circulation [4], a possible genetic predisposition [39], and potentially a specific variant of vitamin D receptor, Klotho, or FGF-23 [4,39]. Further research is required to study whether pHPT is a subcategory of secondary hyperparathyroidism with a different pathophysiology leading to more elevated CCS, or whether higher CCS is merely a consequence of worse metabolic and inflammatory background before KT resulting in a higher rate of pHPT.

The current study showed no significant relation between pHPT and the severity of CAD when assessed by cardiac nuclear stress tests and coronary angiograms. This is likely due to the nature of coronary calcifications in end-stage kidney disease (ESKD) and the propensity for developing medial rather than intimal arterial calcifications, leading to a lower sensitivity and specificity CCS [4,40–44].

Our study has several limitations. First, its retrospective and single-center nature may limit its generalizability. Secondly, CCS was calculated as part of the pre-KT workup but not at the end of the study (12 months after KT). However, this is unlikely to change the validity of our results since KT only slows but does not halt or regress the progression of coronary calcifications for at least the first 2 years after KT [34,45–47].

Despite these limitations, this study included a relatively large sample of KTRs and is one of the few studies to examine the association between CCS and hyperparathyroidism in KTRs. To the best of our knowledge, the association between severe CCS and pHPT is a novel finding. A prospective study with longer follow-up is required to examine the potential causal relation between pHPT and CCS and any potential implications for prevention and treatment.

Conclusions

Severe CCS is associated with pHPT at 12 months after KT, but not PTH serum levels. Further research is needed to explore the complex association between pHPT and coronary calcium deposition in KTRs.