Findings of Cardiovascular Workup of Kidney Transplant Candidates: A Retrospective Study of a Single-Center in Saudi Arabia

Background There are limited data about the prevalence of cardiovascular (CV) risk factors and the findings of CV workup among kidney transplant (KTx) recipients (KTRs) in Saudi Arabia. Methods A single-center retrospective study of KTRs who underwent KTx from 2017 to 2020 was performed. We reviewed the prevalence of CV risk factors and the results of the pre-KTx CV workup which was derived from the American Heart Association guidelines. Results We included 254 KTRs. The mean age was 43.1 ± 15.9 years, and 55.5% were men and 79.5% were living-donor KTRs. Pre-emptive KTx was 9.8%, peritoneal dialysis was 11.8%, and hemodialysis was 78.3% (arteriovenous fistula: 33.1% versus hemodialysis catheter: 66.9%). The mean dialysis vintage was 4.8 ± 3.3 years for deceased-donor KTRs versus 2.4 ± 2.6 years for living-donor KTRs. CV risk factors were hypertension: 76%, diabetes: 40.6% (type 1 : 25.2% versus type 2 : 74.7%), hyperlipidemia (low-density lipoprotein >2.6 mmol/L): 40.2%, coronary artery disease (CAD): 12.6%, smoking: 9.1%, peripheral vascular disease: 2.8%, and cerebral vascular disease: 2.4%. The prevalence of obesity stage 1 was 19.7% and obesity stage 2 was 4%. Left ventricular hypertrophy was present in 38.5%. The ejection fraction was abnormal (<55%) in 22%. Abnormal wall motion was present in 34 patients (13.4%). A cardiac (PET-CT) stress test was conducted on 129 patients (50.8%) which showed abnormal perfusion in 37 patients (28.7%). Out of those who required PET-CT, 18.6% had a coronary artery calcium scoring (CACS) of more than 400, 41.8% had a CACS of zero, 29.4% had a CACS of 1–100, and 14.7% had a CACS of 100–400. Coronary angiogram was required in only 41 patients (16.1%), 12 (29.3%) required coronary interventions, 25 (61%) were treated medically, and 4 (9.8%) did not have any CAD. CT scans of pelvic arteries were performed in 118 patients (46.5%). It showed moderate or severe calcifications in only 7 patients (5.9%), whereas it was normal in 97 patients (82.2%), or it showed only mild calcifications in 14 patients (11.9%). Conclusion This study outlines the prevalence of CV risk factors and the findings of the pretransplant CV workup among KTx candidates who underwent KTx. Multicenter national studies will be helpful to validate the generalizability of these findings.


Background
Tere are currently over 20,000 patients on dialysis in the Kingdom of Saudi Arabia (KSA) [1].Additionally, there are 9,810 patients currently undergoing follow-up after kidney transplant (KTx) [1].Tere were 4,471 new patients starting renal replacement therapy in 2020 with an average annual net increase of 6.2% [2,3].Of the total of 14,190 kidneys transplanted in KSA between 1979 and 2020, 76% were from living donors and 24% were from deceased donors [3].
Chronic kidney disease (CKD) is frequently associated with the traditional cardiovascular (CV) risk factors, such as diabetes mellitus (DM) and hypertension (HTN), and nontraditional CV risk factors such as anemia, hyperparathyroidism, uremia, hypervolemia, infammation, and oxidative stress [4,5].By the time the patients require KTx, many of them have multiple CV risk factors [5].
Given the high prevalence and the atypical presentation of CV disease among KTx candidates [6,7], multiple guidelines recommend CV screening to risk-stratify KTx candidates before surgery [8][9][10][11][12].However, a large degree of variation exists among transplant centers, clinical practice patterns, and clinical guidelines regarding who should be screened and opinions are still based on mixed observational data with a large potential for bias [8][9][10][11][12].Te CV risk assessment of KTx candidates at our center, King Abdulaziz Medical Center, is based mostly on the American Heart Association (AHA) guidelines 2013 [10,13], which is also in line with the most recent KDIGO Guideline 2020 [11,12].
Additionally, data on the CV risk factors and fndings of the CV screening among KTx candidates in Saudi Arabia and the Middle East are limited.Hence, in this study, we examined the prevalence of CV risk factors and the fndings of CV workup of KTx candidates at our center to estimate the CV burden among kidney transplant recipients (KTRs) in KSA.

Methods
A single-center retrospective study of KTx candidates who underwent KTx from January 2017 to May 2020 at King Abdullah International Medical Research Center, Riyadh, KSA, was conducted.After obtaining approval from the Institutional Review Board (IRB) (NRC21R/390/09), we retrospectively reviewed the prevalence of CV risk factors and the results of the pretransplant CV workup.
At our center, screening echocardiograms are performed on all KTx candidates.A cardiac stress test (PET-CT) is performed on those who have ≥3 CV risk factors, limited functional status, or abnormal echocardiogram fndings.Te decision to perform a coronary angiogram difers from cardiology's assessment.In addition, abdominal/pelvic CT scans with intravenous contrast are performed to evaluate the extent of pelvic arterial calcifcations (AC) and atherosclerosis in most KTx candidates.Patients on PD and those who are considered for preemptive transplantation or at a low surgical risk are typically excluded from abdominal/ pelvis CT scanning [13].
All patients who successfully underwent KTx at our center from 2017 to 2020 were included in our analysis.Patients who declined KTx or were transferred to another center before KTx were excluded from the study.Te collected data include the demographics of the KTRs and their traditional CV risk factors (HTN, DM, BMI, CAD, CVA, PVD, and smoking), nontraditional risk factors (parathyroid hormone (PTH) and hemoglobin), and the results of KTx workup including echocardiogram, PET-CT scan, abdominal/pelvic CT scan, and coronary angiogram results (if applicable).

Statistical Analysis
In this current study, we used SPSS version 26 to analyze our data.Descriptive statistics were reported as mean and standard deviation for normally distributed continuous variables and median and interquartile range for nonnormally distributed continuous variables.Categorical variables were reported as frequencies and percentages.To compare continuous variables between two groups, we used the Mann-Whitney U test for nonnormally distributed variables.All p values were two-tailed, and a p value of less than 0.05 was considered statistically signifcant.
Te mean dialysis vintage was 4.8 ± 3.3 years for deceaseddonor KTx versus 2.4 ± 2.6 years for living-donor KTx.Dialysis vintage also varied based on the blood group (Table 2).
Anemia which was defned as hemoglobin <130 g/L in men and 120 g/L in women was present in 67.7% with a mean Hgb of 114.3 ± 17.3.Te mean PTH was 67.8 ± 54.7 (normal: 12.75 pmol/L).

Te Findings of CV Workup of Kidney Transplant
Recipients.Left ventricular hypertrophy (LVH) (mostly mild) was the most common abnormality in our pre-KTx workup (38.5%), followed by abnormal EF defned as EF <55% (22%), and further followed by abnormal wall motion abnormalities (mostly global dyskinesia) which was present in 13.4%.
Cardiac stress testing (PET-CT) was performed on 129 patients (50.8%), and it showed abnormal perfusion in 28.7% of those who had stress tests.Out of those who underwent PET-CT, 24 patients (18.6%) had a calcium score of more than 400, 54 patients (40%) had a calcium score of zero, 38 patients (29.4%) had a calcium score of 1-100, and 19 patients (14.7%) had a calcium score of 100-400.
CT scans of the abdomen and pelvis were performed on 118 patients (46.5%) to assess the suitability of the pelvic vasculatures for transplant.Out of the 118 patients who underwent CT scans, only 7 patients (5.9%) had severely 2 International Journal of Nephrology calcifed vessels, while the remaining scans showed either mild calcifcations (11.8%) or normal studies (82.2%).Table 3 shows the fndings of the CV workup of KTRs.Figures 1-4 show the fndings of pre-KTx screening echocardiography, cardiac PET-CT stress test (cardiac perfusion and CACS), coronary angiogram, and CT angiogram of pelvic arteries, respectively.

Discussion
CV disease is the most common cause of death and hospitalization among end-stage kidney disease (ESKD) patients in KSA and worldwide [14][15][16][17].In KSA, HD patients have high overall rates of hospitalization (11.6 days/patient/ year) and mortality (8.07 deaths per 100 patients per year) [18].CV causes (51.7%) unknown/sudden death (27.5%) and fuid overload are the leading causes of death in these patients [18].KTx decreases the CV risk among these patients [14,15]; however, the risk remains elevated compared to the general population.In fact, CV risk is particularly high in the early post-KTx period, and up to 50% of death within the frst 30 days post-KTx is related to CV events [14,[16][17][18][19][20].Multiple traditional and nontraditional risk factors contribute to this increased risk after KTx [21].Te prevalence of CV risk factors varies based on patients' characteristics, etiology of primary kidney disease, type of transplantation, and dialysis vintage.Similarly, the fndings of CV workups vary based on the screening protocol used by each center.In spite of a relatively high number of KTx performed in KSA since 1979 [3], there are only scant published data about the CV risk assessment of the KTx candidates.
Tis study reviews the CV risk factors of KTRs and the results of their CV workup at a major tertiary transplant center in KSA.Before discussing the CV risk factors and the fndings of pre-KTx workup, there are a few points that are worth noting.First, this study demonstrates that our KTRs are relatively young.Tis fnding is consistent with previous reports that showed that patients in KSA develop ESKD at a relatively younger age than those in Western countries (30% of ESKD patients in the KSA are less than 40 versus 15% in the USA) [3,13].Typically, ESKD patients remain dialysis-dependent unless they undergo KTx [13].However, KTRs are usually younger than the general HD population in KSA (43 versus 51-53 years) [18,22].Tis is likely due to the community's eforts to have younger patients transplanted as soon as possible.
Second, the high rate of living-donor KTx at our center is consistent with the rate (76%) reported nationally [1,3].Yet, the rate of preemptive KTx in KSA is about four times higher than the rate in the USA (9.8 versus 2.5% only) [23].Also, our results showed that ABO blood groups have a major impact on waiting time on deceased donors.We believe that improving the living-donor KTx, particularly for those with certain blood groups, can help shorten the dialysis vintage and subsequently lower the CV risk among KTRs.Note that, the waiting times indicated in our cohort represent the waiting time for those who were successfully transplanted.However, the overall waiting time for the patients on the waiting list is much longer.Tird, consistent with previous reports, the most common causes of ESKD among KTx candidates at our center are DM (25%), unknown (23%), and glomerulonephritis (21%) [13].Tese factors are likely to be the leading causes of ESKD of KTRs in KSA.
Our current study demonstrates the traditional and nontraditional CV risk factors among the Saudi KTRs.Te most common traditional risk factors among our cohort are DM, obesity, HTN, dyslipidemia, smoking, and established CV diseases (CAD, CVA, and PVD).Te nontraditional risk factors include anemia and hyperparathyroidism.
DM, one of the most common traditional CV risk factors, is very prevalent in KSA.Previous studies from KSA noted that DM starts at a younger age leading to higher rates of diabetic microvascular and macrovascular complications [24,25].In addition, type 1 DM seems to be overrepresented International Journal of Nephrology among KTx candidates (10% vs 4.2% of the general HD population), and our study supports this fnding [26].Improving diabetes control and implementing screening and management of diabetic kidney disease can potentially lower the rate of CKD progression and subsequently may improve the CV disease burden.
Our study revealed that the rate of obesity among our KTx candidates is comparable to the rate reported in the general population in KSA [27].However, previous reports have shown that the rate of obesity among Saudi HD patients is lower (11%-23%) [26,28].Tis is probably due to malnutrition among many dialysis patients, particularly those with longer dialysis vintage, whereas KTx candidates constitute a selected healthier subgroup with a better nutritional status.It is also important to note that many KTx centers place their KTx candidates with a high BMI on hold till their weight is optimized to a BMI of ≤35 or ≤37 [29].
Consistent with previous reports, our study demonstrates that HTN is very prevalent among KTx candidates and the control rate remains suboptimal [28].A better HTN control, by adjusting the volume status and titrating the antihypertensive medications, can potentially modify the CV risk.In addition, dyslipidemia is also common among our KTRs and the control rate is similar to those reported among ESRD in KSA (50%) [28].
Te rate of smoking among our KTRs is 9%, which is comparable to the previous reports from KSA [18,26,30].However, this rate is less than the reported rate of smoking among the general Saudi population, where smoking is reported at an overall rate of 19.8% (30.0% in men and 4.2% in women) [31].However, the rate of smoking among our KTRs is comparable to the rate of smoking among American KTRs (11%) [32,33].Note that, smoking cessation is highly encouraged but smoking is not considered an absolute contraindication of KTx at our center.Measures to promote smoking cessation among the CKD population can potentially lower the CV risk.
CAD and CVA are common among HD patients in KSA with a prevalence as high as 11-32.7%and 3.3-11.8%,respectively [18,26,28].Te prevalence of PVD among patients with ESKD in KSA is about 6.4% [28].Tese rates are much less among the selected KTRs.For example, in our cohort of KTRs, PVD was present in only 2% of our participants.Tis is likely because KTx candidates with advanced vascular diseases are often declined.
Anemia and hyperparathyroidism are the most common nontraditional risk factors among our KTRs.According to a national, multicenter study of 389 HD patients throughout KSA, anemia and hyperparathyroidism were controlled in only 50% and 23%, respectively [28].Selected KTx candidates may have more optimized control of their anemia and hyperparathyroidism.Our results support these fndings.
Hemodialysis catheter use among HD patients in KSA is high (31%) [22]; however, the rate of hemodialysis catheter use among KTx candidates is even much higher.Tis is likely due to the tendency to defer arteriovenous fstula (AVF) creation in KTx candidates with available living-donor KTx.Hemodialysis catheters may be considered as a viable bridge therapy option in patients with living donor availability [34].International Journal of Nephrology However, pre-KTx dialysis duration may be quite long even when planned with a living donor [35].Te advantages of protecting these patients from AVF creation must be carefully evaluated against catheter-related risks [35].
As mentioned earlier, the results of the CV workup of KTR candidates vary among centers, based on the studied population and the screening protocol.Te CV risk assessment of KTx candidates at our center is derived mostly from AHA guidelines 2013 [13,36].
Our study is the frst study in KSA to report the pre-KTx echocardiographic fndings even among those who were successfully transplanted.Te most common echocardiographic fndings in our cohort are LVH (38.5%), reduced EF (22%), and wall motion abnormalities (13.4%).
LVH is an adaptive response to increased cardiac work, typically caused by combined pressure and volume overload, resulting in cardiomyocyte hypertrophy and increased intercellular matrix and it is as common as 75% of incident dialysis patients [37].ESKD patients with heart failure (HF) and reduced EF have higher morbidity and mortality rates when compared with those without HF [37].
We found only two studies addressing echocardiographic fndings among ESKD patients in KSA and no other previous studies among KTRs were found.Albeshri et al. studied 333 Saudi HD patients and demonstrated that LV dysfunction (EF <40) was associated with higher morbidity and mortality rates when compared with patients with normal EF [38].In another single-center study of 192 Saudi patients, Sharabas et al. showed that PD patients had higher urine output and better Kt/V values, however, they were more edematous and using more antihypertensive medications and had a lower EF [30].In a study of 356 Spanish patients with CKD awaiting KTx, the most common echocardiographic fndings were LVH in 68.5%, decreased EF in 7.6% (EF 55%-45% in 3.1%, EF 45%-30% in 2.8%, EF <30% in 1.7%), and myocardial contractility alterations in 8.1% [39].
It should be noted that previous reports have shown that LVH was reported in almost 70% of transplant candidates, which is almost twice as high as our study [39,40].Tis could be due to the lower average age of our KTRs (43.1 versus 54.3 years) [40].Also, the availability of living donors that allowed for a higher rate of preemptive transplantation could have contributed to a lower LVH rate by shortening the HD vintage and subsequently lowering the uremiainduced cardiac dysfunction.
Among KTx candidates, LVH, decreased EF, and resting wall motion abnormalities may be related to uremia or CAD [8].At our center, all KTx candidates with a lower EF require cardiologist assessment before KTx.If EF improves to 35% or more, most patients can proceed to transplantation.If EF remains between 25%-35%, we intensify the dialysis regimen for 1 month [41][42][43] and we proceed with KTx if EF improves.If there is no improvement, we obtain cardiology and anesthesia consultations and proceed if the patient accepts high-risk surgery.Patients with EF <25% remain on hold till EF improves [13].Note that, many of these echocardiographic fndings (LVH and EF) improve quickly, within a month following KTx.However, the diastolic dysfunction may not improve signifcantly [40].
Cardiac PET-CT is considered the standard screening tool for KTx candidates with risk factors as mentioned above [13].However, diferent transplant centers in KSA utilize diferent CV screening protocols and imaging modalities.At our center, we follow AHA criteria, and a cardiac PET-CT stress test is performed on those who have at least 3 CV risk factors, limited functional status, or abnormal echocardiogram fndings [13].Te current study represents the frst study in KSA to report cardiac PET-CT results of KTx candidates according to the inclusion criteria of the AHA guidelines.Our results showed that a stress test was required in about 50% of KTx candidates who were successfully transplanted and there were abnormal perfusion results in about a third of those who required it.
We found only one study in KSA by Fathala et al.where asymptomatic ESKD patients referred for KTx at a major tertiary center in KSA were evaluated by a single-photon computed tomography (SPECT) imaging.Te incidence of myocardial perfusion defects was only 13% [44].However, patients with established CAD (having prior percutaneous  International Journal of Nephrology coronary intervention, coronary bypass surgery, or prior myocardial infarction) were excluded.Note that, PET-CT imaging has a much higher sensitivity over SPECT for the diagnosis of CAD [45,46].However, multiple international studies have reported a prevalence of myocardial perfusion abnormalities in ESRD ranging from 27% to 45% based on their population and the inclusion criteria of their local protocol [47][48][49].
In this study, CACS was performed along with cardiac PET-CT in 125 patients (53.1%).Out of those who underwent the CACS test, 54 patients (43.2%) had a calcium score of zero and 24 patients (18.6%) had a calcium score of more than 400.Te absence of CACS in the general population is associated with a low prevalence of obstructive and nonobstructive CAD; and a CACS of zero can serve as a "gatekeeper" for more advanced imaging in the general population [50].On the other hand, CACS is common and more severe in patients with ESKD and can also occur in the absence of occlusive coronary atherosclerosis [51].In ESKD, calcium deposits are not only found in advanced atherosclerotic plaques, as typically seen in the general population, but they also can be deposited heavily in the arterial media [52].CAC also increases arterial stifness and subsequently increases the CV risk [51,53,54].
To the authors' knowledge, this current study is the frst study in KSA to report CACS among KTx candidates who were successfully transplanted.In addition, our study is also the frst study to report the fndings of coronary angiogram among KTx candidates in KSA when applying the AHA protocol.
We found only two studies that reported the fndings of coronary angiograms among KTx candidates in the Gulf area.Te frst study was from a major tertiary center in KSA by Mohamed et al. who retrospectively studied the prevalence of CAD in an asymptomatic cohort of KTx candidates on HD.All included patients underwent coronary angiograms without noninvasive testing.Tey included 368 patients with a mean age of 56 years; of which 25.3% had a prior diagnosis of CAD, 6.8% had previous coronary artery bypass grafting (CABG), 8.4% had previous coronary stents, 78% had DM, 9.5% had prior KTx, 95.7% were on dialysis for >1 year, and 2.5% had a stress test positive for ischemia [61].Out of the 368 patients, 45% had CAD, 17% had 3-vessel disease, 11% had 2-vessel disease, 5.2% had signifcant left main artery narrowing, and 17% had single-vessel disease.Te patients with signifcant 3-vessel disease or left main artery involvement underwent revascularization; and 19% underwent coronary artery bypass grafting, 5% had stenting of the coronary arteries, and 4.7% were on maximal medical therapy [61].Tis study showed that signifcant stenosis of coronary arteries is very prevalent among patients with ESKD who were referred for KTx [61].
Te second study was from Qatar by Ali et al. who prospectively studied 75 ESKD patients, who subsequently underwent KTx.Teir prespecifed protocol utilized noninvasive and/or invasive tests for the evaluation.Te median age of their cohort was 51 years.Overall, 21 (28%) patients showed evidence of CAD, an incidence that was much higher among patients with DM (81%).Tere were 13 (17%) subjects shown to have CAD by coronary angiogram in the absence of a background CAD history [62].
Our results indicate that by applying AHA guidelines among our KTRs, a coronary angiogram was required only in a limited number of patients (16%) and coronary intervention was required only in less than a third of these cases.Te lower rate of CAD among our KTRs is likely due to the younger age of our study participants and the fact that our study included KTx candidates who were healthy enough to get transplanted.To clarify, patients with ESKD who are not referred or excluded from KTx, potentially due to a high CV risk, were not included in the analysis, which can underestimate the overall rate of CAD among the ESKD population.Also, the higher rate of preemptive KTx among our cohort may have lowered the dialysis vintage, meaning that more patients transplanted before they accumulated CV risk.It should be noted that the overall prevalence of CAD in ESKD patients in KSA and internationally can reach up to 20-34% [30,63,64].
CKD patients have an increased incidence of arterial calcifcations (AC).Risk factors include age, male gender, HD, hyperparathyroidism, DM, and dyslipidemia [65,66].Te severity of pelvic AC may impact the surgical planning of KTx, choice of anastomosis site, complexity of the surgery, and eventually patients and grafts survival [65,67].AC is recognized as a good biomarker of the overall CV burden [65].
Žuža et al. retrospectively studied 118 KTRs who underwent pretransplant pelvic CT.Calcifcation morphology, circumference, and length of both common and external iliac arteries were scored.Te pelvic calcium score was calculated as the total score sum of all three calcifcation features in all vessels.AC in at least one vascular segment was found in 79% of patients.Te extent of iliac artery calcifcation in KTx recipients quantifed by pelvic calcium scoring on pretransplant CT correlates with graft and overall patient survival [66].
We found only one retrospective study about AC among 836 HD patients in KSA.Te mean duration since the frst diagnosis of CKD was 8.1 ± 6.3 years and mean dialysis vintage was 5 ± 4.6 years.Te mean age of patients was 51.8 ± 15.4 years.Te prevalence of AC was 40.8% [26].However, CT of pelvic arteries was not utilized in this study as it is of more prognostic relevance to KTx.In our study, the lower rate of calcifcation in pelvic vessels supports the possibility that our cohort was healthier than the average ESKD population in KSA.Again, the younger age and the relatively shorter dialysis vintage because of living donor availability, may have led to such a lower rate.
An international, randomized control study to evaluate the prognostic value of iliac AC determined with CT in patients with KTx is currently underway [68].Tere is also a need to utilize a standardized pelvic calcifcation score International Journal of Nephrology based on the assessment of the common iliac artery and external iliac artery calcifcations, based on their morphology, circumference, and length as proposed by previous studies [68].
In summary, KTRs have a signifcant burden of CV risk factors.Te prevalence of the fndings of their CV workup may vary among centers according to the protocol used.
CV risk assessment of KTx candidates helps to identify patients with CV risk factors that are amenable to interventions that may lower the potential postoperative complications.Screening may also help to exclude very highrisk patients with a nonmodifable disease which may lead to premature graft and patient loss [19,69].
In this study, we reviewed the prevalence of CV risk factors and the fndings of the CV workup of the KTx candidates at our center as an estimate of the CV disease burden among KTRs in KSA.Tis study has several strengths and limitations.First, its single-center, retrospective nature may limit its generalizability.In addition, it included only patients who successfully underwent KTx and did not include those who were not referred for KTx or were declined after workup, which may have underestimated the burden of CV diseases among KTx candidates.
Nevertheless, this study is the frst to highlight in detail the description of CV risk assessment and the fndings of CV workup among KTRs in KSA.Many of these areas have not been previously reported.It is also the frst study in KSA to apply and report the fndings according to the AHA guidelines and consensus guidelines of cardiovascular risk assessment in kidney transplantation in KSA [13,36].Tis step is very essential to create a unifed national approach for the CV risk assessment of KTx candidates and to enable a future multicenter national study to verify these fndings and determine their prognostic values.

Conclusion
Although KTRs are a selected subgroup of the ESKD population, they still carry a signifcant burden of CV risk factors.Tis study outlines the prevalence of CV risk factors among renal transplant candidates along with the fndings of the pretransplant CV workup in a single transplant center in KSA.Having a unifed national approach to the CV risk assessment of KTx candidates among KTx centers in KSA is necessary to enable a multicenter national study which can verify these fndings and determine their prognostic values.

Figure 4 :
Figure 4: Finding of pre-KTx screening CT angiogram of pelvic arteries.

Table 1 :
Characteristics and CV risk factors of KTRs.

Table 2 :
Dialysis vintage and ABO blood groups.

Table 3 :
Findings of CV workup of KTRs.