1 Introduction
Liver transplantation (LT) and kidney transplantation (KT) improve outcomes and quality of life in patients with end-stage liver disease (ESLD)[1] and end-stage renal disease (ESRD).[2] As a result of improved accessibility and recipient survival, transplant candidates are becoming increasingly older, have more comorbidities, and experience more long-term complications, all of which created new challenges in post-transplantation care.
Both LT and KT candidates have complex burdens of cardiovascular disease, at least partly attributed to specific characteristics of ESLD and ESRD. The hyperdynamic circulation in ESLD that was once considered to lower cardiovascular risk can, in combination with poor functional status, mask cardiac conditions during non-invasive cardiac evaluation,[3] traditional cardiovascular risk factors are becoming increasingly prevalent in the aging population of LT candidates, and coronary artery disease is considered to be more common than previously thought.[4] ESRD patients have extremely high cardiovascular morbidity and mortality[5] stemming from a high prevalence of cardiovascular risk factors either as the primary cause of ESRD or part of its clinical manifestation and impaired kidney function in itself causing cardiac dysfunction.[6] In the post-transplant period, a multitude of factors can influence cardiovascular risk in transplant recipients with potential amelioration from adequate graft function after KT, and aggravation in both recipient populations from new-onset dyslipidemia, hypertension, glucose intolerance, and nephrotoxicity as side effects of immunosuppressive agents.[7–10]
Cardiovascular events are recognized as prominent causes of early and late mortality in LT[11–14] and KT recipients.[15–20] To the extent of our knowledge, no previous analyses compared the risk of death from cardiovascular causes in these two patient populations. This study aimed to analyze post-transplant cardiovascular mortality in LT and KT recipients from a single institution. We additionally attempted to identify potential predictors of overall and cardiovascular mortality with cardiovascular factors collected during routine pre-transplant evaluation.
2 Patients and methods
2.1 Patient selection
We retrospectively identified consecutive cases of orthotopic LT from deceased donors and KT from live or deceased donors from a single tertiary center. Adult patients (≥ 18 years) who underwent LT between October 2014 and March 2018 and KT from December 2013 to December 2017 were included in the study. Each patient was reviewed only once. Patients who underwent both LT and KT were excluded.
The study was approved by the University Hospital Merkur ethics committee, and all participants provided informed consent.
2.2 Data collection and follow-up
All recipients underwent preoperative evaluation which excluded patients who fulfilled the criteria for moderate to severe pulmonary hypertension on right heart catheterisation[21] and those with unmanageable active cardiovascular disease. Pre-transplant patient data were acquired from in-hospital electronic records and included demographics, smoking status, relevant comorbid conditions, and time on dialysis. Patients were considered active smokers if they had smoked in the last six months before transplantation. Hypertension was defined as systolic pressure >140 mmHg or diastolic pressure >80 mmHg recorded on more than one out-patient visit or use of antihypertensive medication. Hyperlipidemia was defined as fulfillment of laboratory criteria from a fasting lipid profile with the following cutoff values: triglycerides >1.7 mmol/L (150 mg/dL), total cholesterol >5 mmol/L (193 mg/dL) or low-density lipoproteins >3 mmol/L (116 mg/dL), or use of lipid-lowering agents. Diabetes mellitus (DM) was defined as hemoglobin A1c >6.5%, fasting blood glucose >11mmol/L (126 mg/dL) recorded on more than one occasion, a clinical note of any previous history of DM, or use of oral antihyperglycemic agents or insulin.
Echocardiographic parameters were obtained from 2-D Doppler transthoracic echocardiograms at a single time-point closest to transplantation (no later than 12 months prior), recorded as part of a routine pre-transplant evaluation. 2-D-guided M-mode and biplane Simpson's method were used to assess left ventricular (LV) ejection fraction. LV diastolic function was assessed with mitral inflow velocities and E/A ratio and tissue Doppler imaging of mitral annular motion (the mean value of septal and lateral early diastolic mitral annular velocity e’ and the average E/e’ ratio). Valvular abnormalities were evaluated with color flow Doppler and graded as none/mild/moderate/severe as per guideline recommendations.[22,23] Right ventricular systolic pressure was estimated from tricuspid regurgitation jet velocity with the modified Bernoulli equation and right atrial pressure approximated at 10 mm Hg.
Transplant recipients were followed through out-patient records, in-hospital progress notes, and final discharge summaries from the date of transplantation until the date of death, last follow-up, or June 2019. The primary endpoint was death from cardiovascular causes (cardiac arrest, heart failure, pulmonary embolism, or myocardial infarction); the secondary endpoint was death from any cause.
2.3 Statistical analysis
Collected data were summarized with descriptive statistics (count and frequency for categorical variables, the median and interquartile range for continuous variables). Inter-group comparisons were performed with the χ2 test, Fisher exact test or Mann-Whitney U test. Survival probabilities were estimated with the Kaplan-Meier method and compared with the log-rank test. Cumulative incidence curves were computed to illustrate the risk of death from cardiovascular causes after LT and KT with death from other causes as the competing risk. Gray's modified χ2 test was used to test the equality of cumulative incidence curves between groups.[24]
Additional explorative analyses of potential pre-transplant predictors of overall and cardiovascular mortality after LT and KT were performed with Cox proportional hazards regression. Potential univariable predictors were age at transplantation (continuous), age >60 years, sex, body mass index (BMI) ≥ 30 kg/m2, smoking status, presence of diabetes mellitus, hypertension, hyperlipidemia or peripheral artery disease (PAD), previous cardiovascular incident (myocardial infarction, stroke or transitory ischemic attack), >1 year of dialysis, LV ejection fraction <50%, right ventricular systolic pressure >35 mm Hg, LV diastolic dysfunction grade ≥ 2, aortic stenosis (≥ mild), mitral regurgitation (≥ moderate) and tricuspid regurgitation (≥ moderate). The proportional hazards assumption for each variable was examined graphically with Schoenfeld residuals. Variables with P < .1 at univariable analysis were considered for inclusion in multivariable models. The final model selection was made with backward elimination. Retrospective data collection resulted in some missing data points, which were omitted from the analysis. Statistical significance was established at an α level of .05 throughout the analysis. All P values are based on two-sided tests. The analysis was performed with RStudio for OS X version 1.2.1335 (RStudio Inc.).
3 Results
During the enrolment period, 591 patients underwent either LT or KT. We excluded 14 patients for receiving both LT and KT. Of the 577 patients included in the final analysis, 370 underwent LT and 207 underwent KT. Fifty-one patients (8.8%) were lost to follow-up, 39 in the LT group (10.5%) and 12 in the KT group (5.8%). Thirty-five LT and 2 KT recipients underwent retransplantation during the study period. Participants were predominantly male in both cohorts. Although KT candidates were significantly younger, they had a higher prevalence of hypertension, hyperlipidemia, and PAD. Other pre-transplant patient characteristics are summarized in Table 1 and the underlying causes of ESLD and ESRD in Table 2.
Table 1 -
Pre-transplant patient characteristics.
|
All patients (N = 577) |
LT candidates (n = 370) |
KT candidates (n = 207) |
P value |
| Demographic characteristics |
| Age at transplantation, median (IQR) |
57.6 (48.5-63.5) |
59.3 (52.6-64.4) |
51.7 (40.3-60.9) |
<.001 |
| Age >60 yr |
238/577 (41.2) |
176/370 (47.6) |
62/207 (30.0) |
<.001 |
| Male sex, No. (%) |
402/577 (69.7) |
259/370 (70.0) |
143/207 (69.1) |
.89 |
| Clinical characteristics |
| BMI, median (IQR) |
25.7 (22.8-29.1) |
26.0 (23.1-29.3) |
25.4 (22.4-28.8) |
<.001 |
| BMI ≥ 30 kg/m2, No. (%) |
111/564 (19.7) |
70/361 (19.4) |
41/203 (20.2) |
.90 |
| Current smoker, No. (%) |
144/544 (26.5) |
97/352 (27.6) |
47/192 (24.5) |
.50 |
| Diabetes mellitus, No. (%) |
174/574 (30.3) |
108/368 (29.3) |
66/206 (32.0) |
.56 |
| Hypertension, No. (%) |
358/572 (62.6) |
161/366 (44.0) |
197/206 (95.6) |
<.001 |
| Hyperlipidemia, No. (%) |
288/555 (51.9) |
148/357 (41.5) |
140/198 (70.7) |
<.001 |
| >1 year of dialysis, No. (%) |
170/573 (29.7) |
0 |
170/203 (83.7) |
|
| PAD, No. (%) |
58/575 (10.1) |
15/368 (4.1) |
43/207 (20.8) |
<.001 |
| Previous MI, No. (%) |
25/577 (4.3) |
12/370 (3.2) |
13/207 (6.3) |
.13 |
| Previous CVI or TIA, No. (%) |
21/577 (3.6) |
13/370 (3.5) |
8/207 (3.9) |
>.99 |
| Echocardiographic characteristics |
| LV ejection fraction <50%, No. (%) |
8/561 (1.4) |
4/360 (1.1) |
4/201 (2.0) |
.47 |
| RVSP >35 mmHg, No. (%) |
96/560 (17.1) |
64/359 (17.8) |
32/201 (15.9) |
>.99 |
| LV diastolic dysfunction, grade ≥ 2., No. (%) |
99/559 (17.7) |
68/357 (19.0) |
31/202 (15.3) |
.32 |
| Aortic stenosis, ≥ mild, No. (%) |
37/561 (6.6) |
29/360 (8.1) |
8/201 (4.0) |
.09 |
| Mitral regurgitation, ≥ moderate, No. (%) |
59/561 (10.5) |
39/360 (10.8) |
20/201 (10.0) |
.85 |
| Tricuspid regurgitation, ≥ moderate, No. (%) |
82/561 (14.6) |
58/360 (16.1) |
24/201 (11.9) |
.22 |
BMI = body mass index, CVI = cerebrovascular incident, IQR = interquartile range, KT = kidney transplant, LT = liver transplant, LV = left ventricular, MI = myocardial infarction, PAD = peripheral arterial disease, RVSP = right ventricular systolic pressure, TIA = transitory ischemic attack.
Table 2 -
Indications for liver and kidney transplantation.
| Indication |
No. (%) |
| Liver transplantation∗
,
†, n |
370 |
| Alcoholic liver disease |
160 (43.2) |
| Cryptogenic cirrhosis |
42 (11.4) |
| HCV |
56 (15.1) |
| HBV |
19 (5.1) |
| Biliary cirrhosis |
47 (12.7) |
| HCC |
128 (34.6) |
| Cholangiocarcinoma |
13 (3.5) |
| NASH |
3 (0.8) |
| AIH |
5 (1.4) |
| NET |
6 (1.6) |
| Acute liver failure |
6 (1.6) |
| Other‡
|
12 (3.2) |
| Kidney transplantation, n |
207 |
| Diabetes mellitus |
52 (25.1) |
| Hypertension |
15 (7.2) |
| PKD |
30 (14.5) |
| Glomerulonephritis |
54 (26.1) |
| Pyelonephritis |
3 (1.4) |
| Unknown |
49 (23.7) |
| Other§
|
7 (3.4) |
AIH = autoimmune hepatitis, HCC = hepatocellular carcinoma, HCV = hepatitis C virus, HBV = hepatitis B virus, NASH = non-alcoholic steatohepatitis, NET = neuroendocrine tumor, PKD = adult polycystic kidney disease.
∗More than one indication was documented in some cases.
†One missing datum.
‡Including Wilson's disease, epithelioid hemangioma, α1 antitrypsin deficiency, Budd-Chiari syndrome, adenoma, Caroli disease.
§Including amyloidosis, Balkan endemic nephropathy, multiple myeloma, nephrolithiasis, reflux nephropathy, granulomatosis with polyangiitis.
After a median follow-up of 35.5 months (range 0.4–64.5 months), KT recipients had significantly better post-transplant survival (P = .008) with 1-month, 1-year and 4-year overall survival estimates of 99% (95% CI, 97.7–100%), 95.6% (95% CI, 92.8–98.5%) and 87.7% (95% CI 82.4–93.3%) respectively, while 1-month, 1-year and 4-year estimates for LT recipients were 93.2% (95% CI, 90.7–95.8%), 87% (95% CI, 83.6 - 90.6%), and 83% (95% CI, 79.1–87.1%). We recorded 80 (13.9%) deaths during follow-up, 60 (16.2%) among LT and 20 (9.7%) among KT recipients. Infection was the most common cause of death in both groups in the first post-transplant year and beyond (Tables 3 and 4), followed by graft-related causes and cardiovascular events in LT recipients, while cardiovascular events were the second most common cause of death in KT recipients.
Table 3 -
Causes of death after
liver transplantation.
| Cause of death |
All patients (n = 370) |
<1 yr |
≥ 1 yr |
| Total∗
|
60 |
47 |
13 |
| Cardiovascular†
|
6 (10.0%) |
6 (12.7%) |
0 |
| Cardiac arrest |
4 (6.7%) |
4 (8.5%) |
0 |
| Pulmonary embolism |
2 (3.3%) |
2 (4.3%) |
0 |
| Graft dysfunction |
9 (15.0%) |
5 (10.6%) |
4 (30.8%) |
| Sepsis |
33 (55.0%) |
24 (51.1%) |
9 (69.2%) |
| DIC |
2 (3.3%) |
1 (2.1%) |
1 (7.7%) |
| Hemorrhage |
8 (13.3%) |
7 (14.9%) |
1 (7.7%) |
| Malignancy |
4 (6.7%) |
4 (8.5%) |
0 |
| Unknown |
4 (6.7%) |
3 (6.4%) |
1 (7.7%) |
DIC = disseminated intravascular coagulation.
∗Primary causes of death were classified as either cardiovascular or non-cardiovascular, however more than one non-cardiovascular cause of death was documented in some cases.
†Defined as cardiac arrest, heart failure, pulmonary embolism, myocardial infarction.
Table 4 -
Causes of death after kidney transplantation.
| Cause of death |
All patients (n = 207) |
<1 yr |
≥ 1 yr |
| Total |
20 |
9 |
11 |
| Cardiovascular∗
|
6 (30.0%) |
3 (33.3%) |
3 (27.3%) |
| Cardiac arrest |
2 (10.0%) |
1 (11.1%) |
1 (9.1%) |
| Heart failure |
1 (5.0%) |
0 |
1 (9.1%) |
| Pulmonary embolism |
2 (10.0%) |
1 (11.1%) |
1 (9.1%) |
| Myocardial infarction |
1 (5.0%) |
1 (11.1%) |
0 |
| Sepsis |
9 (45.0%) |
5 (55.5%) |
4 (36.4%) |
| Pneumonia |
1 (5.0%) |
0 |
1 (9.1%) |
| Malignancy |
2 (10.0%) |
0 |
2 (18.2%) |
| Unknown |
2 (10.0%) |
1 (11.1%) |
1 (9.1%) |
∗Defined as cardiac arrest, heart failure, pulmonary embolism, myocardial infarction.
Cumulative incidence curves for cardiovascular mortality computed with death from other causes as the competing risk were not significantly different between groups (P = .36) (Fig. 1). However, the estimated 4-year cumulative cardiovascular mortality probability was higher in KT recipients (3.8% vs. 1.6%). Although cardiovascular mortality in the first 30 days and the first year post-transplant was similar in LT and KT recipients (1.4% vs. 1%; 1.6% vs. 1.5%), no late events (≥ 1 year) were recorded in the LT group as opposed to KT recipients in whom we registered three cardiovascular deaths beyond the first post-transplant year. This difference was more pronounced in a subgroup of older recipients (> 60 years) with 1-year probability 1.7% after LT vs. 3.2% after KT and 4-year probability 2.3% after LT vs. 10.3% after KT (P = .16). No cardiovascular deaths were recorded in younger KT recipients (≤ 60 years) at 1 year vs. 1.0% in LT recipients, and the 4-year probability was similar in both populations with no significant overall difference (1.0% vs. 1.4%, P = .78).
;)
Figure 1: Cumulative incidence curves for cardiovascular mortality after liver and kidney transplantation with death from other causes as the competing risk. CV = cardiovascular, KT = kidney transplantation, LT = liver transplantation.
In univariable Cox proportional hazards analysis, age (continuous), age >60 years, PAD, LV ejection fraction <50%, diastolic dysfunction grade ≥ 2, and ≥ moderate mitral regurgitation were significant risk factors for overall mortality after KT. In a multivariable model age, LV ejection fraction <50% and LV diastolic dysfunction grade ≥ 2 remained significant (Table 5). Of note, the majority (87%) had the pseudonormal pattern (grade 2). In the LT recipient group significant univariable predictors for overall mortality were age >60 years and ≥ moderate tricuspid regurgitation). In an attempt at multivariate modelling both were merely marginally significant (Table 6).
Table 5 -
Pre-transplant variables associated with overall mortality after kidney transplantation.
|
Univariable |
Multivariable |
| Variable |
HR [95% CI] |
P value |
HR [95% CI] |
P value |
| Age (continuous) |
1.1 [1.0–1.1] |
.003 |
1.1. [1.0–1.1] |
.004 |
| Age >60 years |
2.7 [1.1–6.6] |
.03 |
|
|
| PAD |
2.8 [1.1.–6.8] |
.03 |
|
|
| LV ejection fraction <50% |
10.0 [2.3–44.0] |
.002 |
7.6 [1.6–35.5] |
.01 |
| LV diastolic dysfunction, grade ≥ 2 |
4.6 [1.8–11.0] |
.001 |
3.9 [1.5–10.0] |
.004 |
| Mitral regurgitation, ≥ moderate |
3.7 [1.3–10.0] |
.01 |
|
|
LV = left ventricular, PAD = peripheral artery disease.
Table 6 -
Pre-transplant variables associated with overall mortality after
liver transplantation.
|
Univariable |
Multivariable |
| Variable |
HR [95% CI] |
P value |
HR [95% CI] |
P value |
| Age >60 years |
1.8 [1.1–3.1] |
.02 |
1.6 [0.95–2.7] |
.08 |
| Tricuspid regurgitation, ≥ moderate |
1.9 [1.0–3.4] |
.045 |
1.7 [0.95–3.2] |
.07 |
Univariable predictors for cardiovascular mortality following kidney transplantation were similar to those for overall mortality: age (continuous), age >60 years, BMI (continuous), PAD and LV ejection fraction <50%. In a multivariable model PAD and LV ejection fraction <50% remained statistically significant (Table 7). At univariate analysis for cardiovascular mortality in LT recipients, only BMI >30 kg/m2 met the inclusion criteria for a multivariable model, but was not statistically significant (HR 4.1, 95% CI 0.8–20.1, P = .09).
Table 7 -
Pre-transplant variables associated with cardiovascular mortality after kidney transplantation.
|
Univariable |
Multivariable |
| Variable |
HR [95% CI] |
P value |
HR [95% CI] |
P value |
| Age (continuous) |
1.1 [1.0–1.2] |
.04 |
|
|
| Age >60 years |
5.2 [0.95–28.6] |
.06 |
|
|
| BMI (continuous) |
1.1 [1.0–1.3] |
.06 |
|
|
| PAD |
6.2 [1.5–44.8] |
.02 |
7.5 [1.3–42.0] |
.02 |
| LV ejection fraction <50% |
18.0 [1.9–159.0] |
.01 |
10.5 [1.1–97.3] |
.04 |
BMI = body mass index, LV = left ventricular, PAD = peripheral arterial disease.
4 Discussion
The present study showed clear difference with respect to cardiovascular mortality between LT and KT recipients. Although the overall difference in risk of cardiovascular mortality was not significant, most cardiovascular deaths after LT occurred in the immediate perioperative period and were of non-coronary etiology, while both early and late events were captured during follow-up of KT recipients, and all defined causes of cardiovascular mortality were represented. Based on these patterns, one could speculate that continuous and prolonged exposure to numerous traditional and ESRD-specific cardiovascular risk factors affects cardiovascular mortality in KT recipients at all time points as opposed to LT recipients in whom hemodynamic stress of LT mediates early post-transplant cardiovascular risk. On the other hand, long-term cardiovascular risk may be lower in LT patients.
Thirty-day cardiovascular mortality of 1.4% mainly of non-coronary causes in our cohort of LT recipients is in concordance with findings of previous multicentric analyses.[11,12] LT is a high-risk procedure[25] with major volume shifts during clamping of the hepatic vein and graft reperfusion, performed in patients with already altered hemodynamics due to ESLD. Some retrospective studies reported an association of pre-existing coronary artery disease and 30-day cardiovascular mortality,[12] or pre-transplant cardiovascular disease (defined as previous myocardial infarction, PAD, or cerebrovascular disease) and 90-day all-cause mortality.[26] In contrast, others found ESLD- and procedure-related variables to be significantly associated with the risk of perioperative cardiovascular death[11] or a composite outcome of major adverse cardiovascular events.[27,28] Patients with ESLD and very severe cardiovascular comorbidities may be generally discouraged from undergoing LT, but even subclinical disease can be significant in the setting of perioperative stress. Eligibility criteria during preoperative cardiovascular evaluation are still loosely defined and vary between centers and on a case-to-case basis.
Reversibility of ESLD-specific hemodynamic abnormalities or cardiac manifestations such as cirrhotic cardiomyopathy[29] and transitory postoperative disturbances seem to be in line with the pattern of events presented here. We recorded no cardiovascular deaths in LT recipients who survived the first post-transplant year. However, cardiovascular events are consistently among the top five causes of late mortality in LT recipients.[12–14,30] They were also found to be at higher risk for cardiovascular death in the late post-transplant period compared to the age-matched peers without LT.[31] A possible explanation is that long-term atherogenic and diabetogenic adverse effects of calcineurin and mTOR inhibitors[7–9] cumulatively raise cardiovascular risk over time, and the relatively short follow-up of this study may have been too short to capture late cardiovascular mortality. In a retrospective study by Borg et al[32] and a recent study by Koshy et al[12] the time until late death from cardiovascular events was significantly longer compared to that from non-cardiovascular causes. It should also be noted that in our study most LT recipients were on long-term immunosuppression regimens that consisted of a combination of either tacrolimus or cyclosporine with mycophenolate mofetil, which resulted in steroid-sparing. To which such sparing use of corticosteroids, may have potentially produced a more favorable post-transplant cardiovascular risk profile is a matter of speculation.
ESRD patients on dialysis are at a 10 to 20 times higher risk of cardiovascular mortality than the age-, sex-, race- and DM-matched general population.[5] Classic algorithms such as the Framingham risk score still underestimate the risk of ischemic heart disease in KT recipients, indicating excess cardiovascular risk not attributable to traditional risk factors even after successful KT.[33,34] Cardiovascular events are regarded as the most common cause of death at all time points after KT, supported by several population-based studies.[15,16,18] In our cohort, the most frequent cause of death of KT recipients were infective complications both in the first post-transplant year and beyond. Direct comparison of our results with registry data is difficult given the small sample size and single-center setting. However, limitations to these large-scale studies should be noted as well. The analysis from the United States Renal Data System included more than a third of early deaths from unknown or unrecorded causes and even more missing data points over a longer follow-up time.[18] In another US retrospective study with data from an integrated health system different data sources resulted in varying proportions of primary causes of death due to different coding systems.[17] We also enrolled recently transplanted patients. Temporal trends of leading causes of death in KT recipients demonstrate significant risk reduction for cardiovascular mortality and diverging reports regarding mortality from infection.[16,18,19] Improved cardiovascular care and newer immunosuppressive regimens (esp. steroid-sparing protocols) probably have contributed to the decrease in cardiovascular mortality.
In a multivariate model, pre-transplant LV systolic and diastolic dysfunction in KT candidates were independent risk factors for all-cause mortality after transplantation. Although KT was found to improve systolic function,[35,36] functional status, and survival[35] in ESRD patients with congestive heart failure in a prospective setting, adequately powered prospective controlled trials evaluating safety of KT in patients with various degrees of systolic heart dysfunction are lacking. On the other hand, reports on changes in LV diastolic function after KT vary.[37–39] In order to reduce negative impact of impaired systolic and diastolic heart function on post-transplant outcomes, waiting time should be shortened as much as is possible (e.g. by promoting pre-emptive and living-donor transplantation). Good control of blood pressure and optimizing graft function represent additional potentially modifiable factors for reversal of cardiac dysfunction after KT,[40] thus leading to improvement of post-transplant cardiovascular risk.
Traditional cardiovascular risk factors were not significant predictors of overall mortality in either LT or KT recipients. Similarly, PAD (a marker for generalized atherosclerosis) was a significant risk factor for cardiovascular mortality after KT, but DM, hypertension or hyperlipidemia were not independent predictors in either cohort. Since the cardiovascular risk profile of transplant recipients undergoes dynamic changes after transplantation with a high incidence of post-transplant metabolic syndrome and its components,[41,42] post-transplant risk profiling could have a better predictive value for both overall and cardiovascular mortality.
This study's single-center nature introduces limitations in generalizability as patient selection and immunosuppressive regimens may vary between institutions. It is also subject to pitfalls inherent to all retrospective and observational studies such as missing data which might have diminished the already comparably small sample size's statistical power. We attribute the loss to follow-up encountered (8.8% of the total study population) to the division of recipient care to other smaller institutions as the data source were in-hospital electronic records from a tertiary transplant center. Participants who underwent retransplantation during the study period were predominantly LT recipients, the majority of whom experienced graft failure within the first post-transplant year and did not influence the primary outcome of cardiovascular mortality as we recorded no late cardiovascular deaths that could be potentially attributed to early postoperative stress after a second transplantation. We also recognize certain limitations regarding variable selection and definition. LV mass was not in the pre-specified scope of data collection, and LV hypertrophy could be an overlooked confounding factor between diastolic dysfunction and overall mortality given the probable etiological overlapping, high prevalence in ESRD,[43] and previous association with mortality after KT.[44] Our definitions of DM, hypertension, and hyperlipidemia which encompassed patient history and treatment records as well as records of physical and laboratory measurements may have been insufficiently precise in depicting blood pressure, glycemic and lipid control.
In summary, while this study failed to demonstrate a significant difference in the overall risk of cardiovascular death in LT and KT recipients, a more nuanced interpretation can reveal distinctions in temporal and causative patterns of cardiovascular mortality in these two populations. Cardiovascular causes contribute to early mortality both in LT and KT recipients, and late cardiovascular mortality seems to be higher in KT recipients than LT recipients, the latter warranting further investigation over a longer follow-up time and in a larger study sample. These findings stress the already recognized need for an individualized approach in investigating pre-transplant risk and providing post-transplant cardiovascular care. Prospective studies in a randomized setting that would help identify high-risk groups and optimize outcomes in transplant recipients are still generally lacking and much needed.
Author contributions
Conceptualization: Helena Jerkić.
Data curation: Zrinka Sertić, Tomislav Letilović, Inga Starovečki, Helena Jerkić.
Formal analysis: Zrinka Sertić.
Investigation: Zrinka Sertić, Tomislav Letilović, Tajana Filipec Kanižaj, Mladen Knotek, Irzal Hadžibegović, Inga Starovečki, Helena Jerkić.
Methodology: Zrinka Sertić.
Project administration: Helena Jerkić.
Resources: Tomislav Letilović, Tajana Filipec Kanižaj, Mladen Knotek, Irzal Hadžibegović, Helena Jerkić.
Supervision: Tomislav Letilović, Mladen Knotek.
Validation: Tajana Filipec Kanižaj, Mladen Knotek, Irzal Hadžibegović, Inga Starovečki, Helena Jerkić.
Visualization: Zrinka Sertić.
Writing – original draft: Zrinka Sertić.
Writing – review & editing: Zrinka Sertić, Tomislav Letilović, Mladen Knotek, Helena Jerkić.
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