Silent cardiac burden: Echocardiographic abnormalities and their predictors in kidney transplant candidates and their impact on graft function

Abstract

BACKGROUND

An echocardiogram is an essential tool in the evaluation of potential kidney transplant recipients (KTRs). Despite cardiac clearance, potential KTRs still have structural and functional abnormalities. Identifying the prevalence of these abnormalities and understanding their predictors is vital for optimizing pre-transplant risk stratification and improving post-transplant outcomes.

AIM

To determine the prevalence of left ventricular hypertrophy (LVH), left ventricular systolic dysfunction (LVSD), diastolic dysfunction (DD), pulmonary hypertension (PH), and their predictors, and to assess their impact on graft function in pre-transplant candidates.

METHODS

The study included all successful transplant candidates older than 14 who had a baseline echocardiogram. Binary logistic regression models were constructed to identify factors associated with LVH, LVSD, DD, and PH.

RESULTS

Out of 259 patients, LVH was present in 64% (166), 12% (31) had LVSD, 27.5% (71) had DD, and 66 (25.5%) had PH. Independent predictors of LVH included male gender [odds ratio (OR): 2.51; 95%CI: 1.17–5.41 P = 0.02], PH (OR = 2.07; 95%CI: 1.11–3.86; P = 0.02), DD (OR: 2.47; 95%CI: 1.29–4.73; P = 0.006), and dyslipidemia (OR = 1.94; 95%CI: 1.07–3.53; P = 0.03). Predictors for LVSD included patients with DD (OR = 3.3, 95% CI: 1.41–7.81; P = 0.006) and a family history of coronary artery disease (OR = 4.50, 95%CI: 1.33–15.20; P = 0.015). Peritoneal dialysis was an independent predictor for DD (OR = 10.03; 95%CI: 1.71-58.94, P = 0.011). The presence of LVH (OR = 3.32, 95%CI: 1.05–10.55, P = 0.04) and mild to moderate or moderate to severe mitral regurgitation (OR = 4.63, 95%CI: 1.45–14.78, P = 0.01) were significant factors associated with PH. These abnormalities had no significant impact on estimated glomerular filtration at discharge, 6 months, 1 year, or 2 years post-transplant.

CONCLUSION

Significant echocardiographic abnormalities persist in a potential transplant candidate despite cardiac clearance, although they don’t affect future graft function. Understanding the risk factors associated with these abnormalities may help clinicians address these factors pre- and post-transplant to achieve better outcomes.

Key Words: Echocardiographic abnormalities; Kidney transplant; Predictors; Graft function

Core Tip: Despite clearance by a cardiologist, kidney transplant recipients have structural and functional abnormalities. These abnormalities may partially resolve after transplantation, but not wholly. Abnormalities such as left ventricular hypertrophy, left ventricular systolic dysfunction, diastolic dysfunction, pulmonary hypertension may have an impact on graft and patient survival. Understanding their predictors may help alleviate these abnormalities and improve patient and graft survival. This will enable clinicians to devise a pathway to reduce cardiovascular events, improve long-term graft function, and decrease mortality.

INTRODUCTION

Patients with end-stage renal disease (ESRD) on hemodialysis have a 10-20-fold higher risk of cardiovascular diseases[1]. Kidney transplantation significantly reduces the risk, although it is still higher than that of the general population. Kidney transplant recipients (KTRs) have 10 times higher cardiac death rates than the general population. Furthermore, the annual rate of fatal and nonfatal cardiovascular events is 50 times higher than that of the general population[2]. Cardiovascular disease is one of the common reasons that lead to hospitalization in 30% of the cases, and, more alarmingly, 4% of these patients die[3]. Cardiovascular disease is also the leading cause of death, with a functioning graft loss accounting for 36.3%[4]. Therefore, doing an extensive cardiac workup pre-transplant is essential to ensure a better outcome in the future.

The heart undergoes structural changes in patients on hemodialysis. Patients with chronic kidney disease (CKD) develop left ventricular hypertrophy (LVH), left ventricular systolic dysfunction (LVSD), diastolic dysfunction (DD), pulmonary hypertension (PH), during their progression to ESRD. In 20% of cases, early CKD patients have LVH[5], but the prevalence goes up to 70%-80% in ESRD patients[6,7]. Similarly, DD is present in 70%-85% of patients with CKD[8,9]. The literature has reported LVSD in 22% of the cases in ESRD patients[9]. ESRD patients also develop PH, and the prevalence has been reported to be up to 80%[10]. Considering these facts, ESRD patients need an echocardiogram for structural and functional assessment. Despite cardiac clearance, we have observed that these patients have structural and functional abnormalities on echocardiography. Although these findings may not disqualify patients from undergoing transplantation, they may contribute to future cardiovascular events and may have prognostic significance. Identifying the predictors for these structural and functional abnormalities could help to adopt strategies to refine cardiovascular risk and improve patient and graft outcomes. This retrospective study examined the prevalence of LVH, DD, LVSD, and PH as well as their predictors in ESRD patients who underwent live-related kidney transplantation.

MATERIALS AND METHODS

Setting and study population

This retrospective observational study was conducted at the Centre of Renal Diseases and Transplantation at King Fahad Armed Forces Hospital, Jeddah. Our unit performs 70-90 kidney transplants per year. After the approval of the ethics review committee, data were collected for three years, between 2021 and 2024, for all patients who underwent live-related transplantation. All patients had a baseline electrocardiogram and echocardiogram. Those above 60, patients with diabetes aged 50 years or above, and those with an echocardiogram showing a low ejection fraction or regional wall abnormality underwent further testing, such as an exercise tolerance test or coronary angiogram. A convenience sampling method was used. As this study included all available cases during the study period, a formal sample size calculation was not performed.

We included all patients who underwent live-related kidney transplantation between January 2021 and December 2024 and had a transthoracic echocardiogram available at or within three months before the time of transplantation. Patients were excluded if they had no echocardiographic data or were younger than 14 years of age at the time of transplant. The donor was either a biological relative within the fourth degree of kinship or the spouse of the recipient, and was ≥ 18 years of age. To minimize selection and information bias, all eligible kidney transplant candidates evaluated during the study period were included, and data were obtained from standardized pretransplant echocardiographic and clinical records using uniform definitions.

Demographic and relevant laboratory data, as well as echo details, were collected from centralized computerized records and charts on a standardized form. All echocardiographic examinations were performed pre-transplantation, approximately one month before surgery. Echocardiograms were conducted post-dialysis, at a time when patients were close to their dry weight to minimize the influence of volume overload on cardiac parameters. We used an operational definition for DD, LVSD, and PH. DD was graded as grade 1 (mild DD or impaired relaxation phase), grade 2 (moderate DD or pseudonormal phase), and grade 3 (severe DD or restrictive filling phase)[11]. DD was assessed using the E/A ratio, E/e′ ratio, left atrial volume index, and tricuspid regurgitation (TR) velocity. LVSD was defined as mild with an ejection fraction of 40%-49%, moderate 30%-39%, and severe < 30%[12]. PH was classified as mild 20-40 mmHg, moderate = 41-55 mmHg, and severe > 55 mmHg[13]. PH was estimated using echocardiography to measure the peak velocity of the TR jet. Mitral regurgitation (MR) was graded as mild (grade 1), mild to moderate (grade 2), moderate to severe (grade 3), and severe (grade 4) according to the American Society of Echocardiography guidelines. TR was also classified as mild (grade 1), mild to moderate (grade 2), moderate to severe (grade 3), and severe (grade 4) according to the American Society of Echocardiography guidelines. Similarly, aortic regurgitation (AR) was classified as mild (grade 1), moderate (grade 2), and severe (grades 3 and 4)[14]. Pericardial effusion was classified as mild, less than 10 mm, moderate, 10-20 mm, and large effusions, greater than 20 mm. To understand LVH, DD, LVSD, and PH, and their predictors, each condition was compared with patients who did not have these abnormalities.

Statistical analysis

Descriptive statistics for both quantitative and qualitative data were expressed as mean, median, interquartile range, standard deviation, and number of observations, along with the percentage (%). As this was a retrospective study, all available clinical, laboratory, and echocardiographic variables were analyzed. Missing data were not imputed; analyses were performed using the available information for each variable. Univariate analysis was performed to identify factors associated with LVH, DD, LVSD, and PH using the χ² test and Fisher's exact test for independence to compare proportions where appropriate, and the Student’s t-test was used to analyze continuous data. OR and their 95%CI were estimated using binary logistic regression to identify predictors of LVH, DD, LVSD, and PH. Although no formal sensitivity analysis was performed, the stability of associations was assessed by comparing results from univariate and multivariate models. All P-values were based on two-sided tests, and significance was set at a P value < 0.05. The analyses were performed using SPSS version 19.

RESULTS

General characteristics

A total of 259 KTRs were included in the study. A flow diagram was not included as the study design involved retrospective review of a defined cohort, and inclusion/exclusion criteria were applied directly during data extraction. As this was a retrospective analysis, all available data were included for analysis. The number and percentage of participants with available information for each variable are shown in the tables. Most of the patients, accounting for 58%, were aged between 14 and 50 years. The bulk of the KTRs (158, 61%) were male. A family history of diabetes was present in 113 (44%) patients. In terms of morbidities, hypertension, dyslipidemia, smoking, and obesity were present in 97%, 37%, 47%, and 35%, respectively. One hundred and thirty-one (51%) KTRs had impaired fasting glucose, and 20 (8%) had a family history of coronary artery disease. Regarding renal replacement therapy, 208 (81%) were on hemodialysis and 36 (14%) were on peritoneal dialysis. Fourteen (5%) underwent pre-emptive transplantation. The duration of renal replacement therapy was 22.65 ± 21.90 months. The mean total cholesterol was 4.41 ± 1.16 mmol/L. The mean parathyroid hormone level was 26.29 ± 26.67 pmol/L, and the mean phosphate level was 1.54 ± 0.56 mmol/L. Estimated glomerular filtration (eGFR) was 89.83, 89.58, 91, and 90.26 mL/minute at discharge, 6 months, 1 year, and 2 years, respectively. Table 1 shows general characteristics of KTRs, and Table 2 shows their echocardiographic findings.

Table 1 General characteristics.

Variables	n	Percentage (%)/mean ± SD
Age
18-50 years	149	58
> 50 years	110	42
Gender
Male	158	61
Female	101	39
BMI at time of transplant
< 25	123	47
25-30	76	29
> 30	60	23
Hypertension	252	97
Dyslipidemia	97	37
Smoking	121	47
Hyperuricemia	78	30
Impaired fasting glucose	131	51
Family history of coronary artery disease	20	8
Obesity	90	35
Renal replacement therapies
Preemptive transplant	14	5
Hemodialysis	208	81
Peritoneal dialysis	36	14
PH	66	25.5
DD	71	28
LVSD	31	12
Duration of dialysis in months	242	22.65 ± 21.90
Total cholesterol (mmol/L)	258	4.41 ± 1.16
LDL-cholesterol (mmol/L)	258	2.69 ± 2.02
HDL-cholesterol (mmol/L)	258	1.29 ± 0.49
Triglyceride (mmol/L)	258	1.61 ± 1.14
eGFR at discharge (mL/minute)	258	89.83 ± 30.69
eGFR at 6 months (mL/minute)	252	89.58 ± 28.99
eGFR at 1 year (mL/minute)	216	91.00 ± 26.92
eGFR at 2 years (mL/minute)	122	90.26 ± 26.76

BMI: Body mass index; DD: Diastolic dysfunction; eGFR: Estimated glomerular filtration rate; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; LVSD: Left ventricular systolic dysfunction; PH: Pulmonary hypertension.

Table 2 Echocardiographic findings.

Variables	n	Percentage (%)
LVH	92	36
LVSD
Ejection fraction 50% or more	226	87.9
Mild dysfunction LVSD 40%-49%	23	8.9
Moderate dysfunction LVSD 30%-39%	7	2.7
LVSD less than 30%	1	0.4
DD
Impaired relaxation	60	85
Pseudonormal filling	10	14
Restrictive filling	1	1
PH in mmHg
Mild 20-40 mmHg	52	72.8
Moderate 41-55 mmHg	12	18.2
Severe > 55 mmHg	2	3
MR (grades)
Mild	126	56
Mild to moderate	94	22
Moderate to severe	4	2
Mitral stenosis
Yes	1	1
No	256	99
TR (grades)
Mild	150	90
Moderate	15	9
Severe	1	1
AR (grades)
Mild	43	96
Moderate	2	4
Aortic stenosis (grades)
Mild	3	100
Moderate	0	0
Severe	0	0
Pericardial effusion (grades)
Mild, less than 1 mm	38	88
Moderate 1-2 mm	5	12
Large, more than 2 mm	0	0

AR: Aortic regurgitation; DD: Diastolic dysfunction; LVH: Left ventricular hypertrophy; LVSD: Left ventricular systolic dysfunction; MR: Mitral regurgitation; PH: Pulmonary hypertension; TR: Tricuspid regurgitation.

Echocardiography finding

All echocardiographic assessments were performed within a standardized timeframe, approximately one month before transplantation and post-dialysis sessions, when patients were at or near dry weight. This timing was intended to reduce the confounding effects of volume status on cardiac measurements. We found LVH in 92 (36%) of the patients. Most patients (226, 87.9%) had normal systolic function, with an ejection fraction of 50% or greater. Approximately 12% (31) had LVSD. Twenty-three (8.9%) had mild LVSD, 7 (2.7%) had moderate LVSD with an ejection fraction of 30%-39%, and only one (0.4%) had severe LVSD with an ejection fraction of less than 30%. Around 71 (28%) had DD. Among patients with DD, 60 (85%) had grade 1, 10 (14%) had grade 2, and one (1%) had grade 3 DD. Around 66 (25.5%) had PH. Fifty-two (78.8%) had mild PH, 12 (18.2%) had moderate PH, and two (3%) had severe PH. MR was the typical lesion present in 224 (86.8%). Grade 1 MR was present in 126 (56%), 94 (42%) had grade 2 MR, and 4 (2%) had grade 3 MR. TR was the next most common valvular lesion, present in 166 (64.3%), followed by AR in 45 (17.4%), aortic stenosis in three (1.2%), and mitral stenosis in one (0.38%). We found pericardial effusion in 43 (16.6%), with mild pericardial in 38 (88%), and five (12%) had moderate pericardial effusion.

Predictors of LVH, LVSD, DD, and PH

LVH: Multivariate analysis identified various factors associated with LVH. The odds of having LVH were higher in males than females (OR: 2.51; 95%CI: 1.17–5.41; P = 0.02). Other significant predictors for LVH included PH (OR: 2.07; 95%CI: 1.11–3.86; P = 0.02), DD (OR: 2.47; 95%CI: 1.29–4.73; P = 0.006), and dyslipidemia (OR: 1.94; 95%CI: 1.07–3.53; P = 0.03). We did not find a significant association of LVH with age, obesity, various valvular regurgitations, hypertension, smoking status, diabetes, impaired fasting glucose, hyperuricemia, family history of coronary artery disease, or dialysis modality. Table 3 shows predictors of LVH.

Table 3 Predictors of left ventricular hypertrophy, n (%)/mean ± SD.

Variables	Univariate analysis			Multivariate analysis
	LVH	No LVH	P value	OR (95%CI)	P value
Age			0.28
18-50 years	49 (33)	100 (67)
> 50 years	43 (39)	66 (61)
Gender			0.004	2.51 (1.17-5.41)	0.02
Male	76 (42)	91 (58)
Female	25 (25)	75 (75)
Obesity	29 (33)	60 (67)	0.49
BMI ranges			0.78
< 25	46 (38)	76 (62)
25-30	25 (33)	51 (67)
> 30	21 (35)	39 (65)
PH	34 (52)	58 (30)	0.002	2.07 (1.11-3.86)	0.02
Mitral regurgitation (grade 2-4)	49 (39)	33 (35)	0.56
Tricuspid regurgitation	33 (37)	59 (36)	0.89
Aortic regurgitation	18 (40)	74 (35)	0.61
LVSD	17 (55)	14 (45)	0.016	2.11 (0.89-5.02)	0.09
DD	38 (54)	33 (46)	< 0.001	2.47 (1.29-4.73)	0.006
MR (grade 2-3)	49 (39)	77 (61)	0.58
TR	59 (36)	107 (64)	0.89
AR	18 (40)	27 (60)	0.61
Hypertension	91 (36)	160 (64)	0.43
Pericardial effusion	18 (44)	33 (56)	0.24
Dyslipidemia	46 (48)	50 (52)	0.002	1.94 (1.07-3.53)	0.03
Smoking	49 (40)	72 (60)	0.13	0.46 (0.36-1.58)	0.46
Diabetes	15 (44)	19 (56)	0.27
Impaired fasting glucose	55 (42)	75 (58)	0.03	1.38 (0.76-2.50)	0.30
Hyperuricemia	27 (35)	50 (65)	0.90
Duration of dialysis in months	22.23 ± 19.71	23.00 ± 23.15	0.79
Total-cholesterol (mmol/L)	4.49 ± 1.27	4.36 ± 1.09	0.40
LDL cholesterol (mmol/L)	2.93 ± 3.16	2.55 ± 0.90	0.26
HDL cholesterol (mmol/L)	1.25 ± 0.50	1.23 ± 0.49	0.74
Triglyceride (mmol/L)	1.72 ± 1.17	1.54 ± 1.12	0.23
Phosphate (mmol/L)	1.54 ± 0.56	1.53 ± 0.57	0.88
PTH (pmol/L)	22.68 ± 25.95	29.52 ± 27.12	0.17	1.00 (0.98-1.02)	0.79
Family history of coronary artery disease	4 (20)	16 (80)	0.13	0.37 (0.11-1.30)	0.12
Pre-emptive transplant	6 (43)	8 (57)	0.82
Hemodialysis	74 (36)	133 (64)
Peritoneal dialysis	12 (33)	24 (67)

AR: Aortic regurgitation; DD: Diastolic dysfunction; LVH: Left ventricular hypertrophy; LVSD: Left ventricular systolic dysfunction; MR: Mitral regurgitation; PH: Pulmonary hypertension; TR: Tricuspid regurgitation.

LVSD: The multivariate analysis showed various predictors for LVSD. Patients with DD had an odds ratio of 3.33 (95%CI: 1.41–7.81; P = 0.006). This means that patients with DD are over three times more likely to develop LVSD. A family history of coronary artery disease was also found to be a significant predictor, with an odds ratio of 4.50 (95%CI: 1.33-15.20; P = 0.015). This highlights the significance of genetic predisposition in the development of LVSD. LVH and grade 2-3 MR showed a potential association with LVSD, although findings did not reach statistical significance. Other factors such as age, gender, obesity, hypertension, diabetes, and smoking also did not show significant associations with LVSD. These findings suggest that DD and a family history of coronary artery disease play an essential role in the causation of LVSD. Table 4 shows predictors of LVSD.

Table 4 Predictors of left ventricular systolic dysfunction, n (%)/mean ± SD.

Variables	Univariate analysis			Multivariate analysis
	LVSD	No LVSD	P value	OR (95%CI)	P value
Age			0.71
18-50 years	17 (11)	132 (89)
> 50 years	14 (13)	94 (87)
Gender			0.42
Male	21 (13)	136 (87)
Female	10 (10)	90 (90)
Obesity	13 (15)	76 (85)	0.37
BMI ranges			0.58
< 25	15 (12)	106 (88)
25-30	7 (9)	69 (91)
> 30	9 (15)	51 (85)
PH	9 (14)	57 (86)	0.65
DD	18 (26)	52 (74)	< 0.001	3.33 (1.41-7.81)	0.006
LVH	17 (19)	74 (81)	0.016	2.33 (0.97-5.60)	0.058
MR (Grade 2-3)	22 (18)	104 (82)	0.04	2.38 (0.93-6.12)	0.07
TR	23 (14)	142 (86)	0.32
AR	7 (16)	38 (84)	0.20
Hypertension	31 (12)	219 (88)	> 0.999
Pericardial effusion	9 (22)	32(78)	0.06	1.78 (0.67-4.77)	0.25
Dyslipidemia	26 (27)	70 (73)	0.90
Smoking	18 (15)	102 (85)	0.18	1.55 (0.64-3.76)	0.33
Diabetes	5 (15)	29 (85)	0.58
Impaired fasting glucose	15 (12)	114 (88)	0.83
Hyperuricemia	12 (16)	65 (84)	0.26
Duration of dialysis in months	18.62 ± 8.67	23.22 ± 23.15	0.045	0.98 (0.96-1.01)	0.24
Total cholesterol (mmol/L)	4.30 ± 1.11	4.41 ± 1.16	0.63
LDL-cholesterol (mmol/L)	3.34 ± 5.20	2.59 ± 0.99	0.43
HDL-cholesterol (mmol/L)	1.25 ± 0.59	1.23 ± 0.48	0.81
Triglycerides (mmol/L)	1.83 ± 1.36	1.58 ± 1.11	0.24
Mean phosphate (mmol/L)	1.60 ± 0.48	1.52 ± 0.58	0.54
Mean PTH (pmol/L)	22.81 ± 24.26	27.2 ± 27.26	0.49
Family history of coronary artery disease	6 (30)	14 (70)	0.02	4.50 (1.33-15.20)	0.015
Pre-emptive transplant	1 (7)	13 (93)	0.87	0.98 (0.96-1.01)	0.24
Hemodialysis	25(12)	181 (88)
Peritoneal dialysis	5 (14)	31 (86)

AR: Aortic regurgitation; BMI: Body mass index; DD: Diastolic dysfunction; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; LVH: Left ventricular hypertrophy; LVSD: Left ventricular systolic dysfunction; MR: Mitral regurgitation; OR: Odds ratio; PTH: Parathyroid hormone; PH: Pulmonary hypertension; TR: Tricuspid regurgitation.

DD: Although univariate analysis identified various factors associated with DD, logistic regression analysis revealed only peritoneal dialysis as an independent risk factor for DD (OR = 10.03, P = 0.011). Other variables, including LVSD, MR, and LVH, showed a trend toward association but did not reach statistical significance in multivariate analysis. Table 5 shows predictors of DD.

Table 5 Predictors of diastolic dysfunction, n (%)/mean ± SD.

Variables	Univariate analysis			Multivariate analysis
	DD	No DD	P value	OR (95%CI)	P value
Age			< 0.001	1.51 (0.49-4.60)	0.48
18-50 years	25 (17)	124 (83)
> 50 years	46 (42)	63 (58)
Gender
Male	46 (29)	112 (71)	0.47
Female	25 (25)	75 (75)
Obesity	27 (30)	62 (70)	0.48
BMI ranges			0.45
< 25	31 (25)	91 (75)
25-30	25 (33)	51 (77)
> 30	15 (25)	45 (75)
PH	21 (32)	45 (68)	0.37
LVSD	18 (58)	13 (42)	< 0.001	3.50 (0.98-12.51)	0.054
LVH	38 (41)	54 (59)	< 0.001	1.76 (0.70-4.41)	0.23
MR (grade 2-3)	44 (35)	82 (65)	0.37	1.84 (0.73-4.65)	0.20
TR	51 (31)	115 (69)	0.19	1.94 (0.69-5.50)	0.21
AR	16 (36)	29 (64)	0.20	1.26 (0.43-3.70)	0.67
Hypertension	71 (28)	180 (72)	0.20
Pericardial effusion	19 (46)	22 (54)	0.003	1.58 (0.50-4.98)	0.44
Dyslipidemia	26 (27)	70 (73)	0.90
Smoking	39 (32)	82 (68)	0.11	0.98 (0.39-2.48)	0.96
Diabetes	11 (32)	23 (68)	0.50
Impaired fasting glucose	50 (38)	80 (62)	< 0.001	1.74 (0.56-5.42)	0.34
Hyperuricemia	23 (30)	54 (70)	0.58
Duration of dialysis in months	24.96 ± 25.04	21.82 ± 20.55	0.32
Total cholesterol (mmol/L)	4.37 ± 1.13	4.42 ± 1.17	0.78
LDL-cholesterol (mmol/L)	2.88 ± 3.50	2.61 ± 1.01	0.34
HDL-cholesterol (mmol/L)	1.27 ± 0.55	1.22 ± 0.47	0.53
Triglyceride (mmol/L)	1.64 ± 1.22	1.59 ± 1.11	0.76
Mean phosphate level (mmol/L)	1.57 ± 0.57	1.50 ± 0.57	0.50
Family history of coronary artery disease	8 (40)	12 (60)	0.20	0.71 (0.16-3.14)	0.65
Mean PTH level (pmol/L)	21.46 ± 21.77	30.49 ± 29.65	0.06	0.11 (0.98-0.96)	1.00
Pre-emptive transplant	1 (7)	13 (93)	0.17	10.03 (1.71-58.94)	0.001
Hemodialysis	58 (28)	149 (72)
Peritoneal dialysis	12 (33)	24 (67)

AR: Aortic regurgitation; BMI: Body mass index; DD: Diastolic dysfunction; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; LVH: Left ventricular hypertrophy; LVSD: Left ventricular systolic dysfunction; MR: Mitral regurgitation; OR: Odds ratio; PTH: Parathyroid hormone; PH: Pulmonary hypertension; TR: Tricuspid regurgitation.

PH: We found that LVH and grade 2-3 MR were independently associated with PH. Presence of LVH had 3.32-fold increased odds of PH (OR = 3.32, 95%CI: 1.05–10.55, P = 0.04). Conversely, grade 2-3 MR had 4.63-fold increased odds (OR = 4.63, 95%CI: 1.45–14.78, P = 0.01) of having PH. TR showed a trend toward association with PH but failed to attain statistical significance. Similarly, other variables such as obesity, BMI, AR, coronary revascularization, pericardial effusion, dyslipidemia, diabetes mellitus, family history of coronary artery disease, and mean phosphate levels were not significantly associated with PH. Table 6 shows predictors of pulmonary hypertension.

Table 6 Predictors of pulmonary hypertension, n (%)/mean ± SD.

Variables	Univariate analysis			Multivariate analysis
	PH	No PH	P value	OR (95%CI)	P value
Age			0.23
18-50 years	34 (23)	115 (77)
> 50 years	32 (29)	77 (71)
Gender
Male	44 (28)	114 (72)	0.29
Female	22 (22)	78 (78)
Obesity	12 (13)	88 (87)	0.001	0.29 (0.05-1.69)	0.17
BMI ranges			0.03
< 25	40 (33)	82 (67)
25-30	17 (22)	59 (78)		0.79 (0.22-2.79)	0.71
> 30	9 (15)	51 (75)		0.85 (0.10- 7.55)	0.88
DD	21 (30)	50 (70)	0.37
LVSD	9 (29)	22 (71)	0.65
LVH	34 (37)	58 (63)	0.02	3.3 (1.05-10.55)	0.04
MR (grade 2-3)	45 (36)	81 (64)	< 0.001	4.6 (1.45-14.78)	0.01
TR	51 (31)	115 (69)	0.01	3.70 (0.93-14.69)	0.06
AR	18 (40)	27 (60)	0.02	0.57 (0.16-2.00)	0.38
Hypertension	64 (25)	187 (75)	0.99
Pericardial effusion	17 (41)	224 (59)	0.012	2.28 (0.63-8.31)	0.21
Dyslipidemia	31(32)	65 (68)	0.057	2.80 (0.80-9.81)	0.11
Smoking	29 (24)	92 (76)	0.58
Diabetes	4 (12)	30 (88)	0.048	0.79 (0.16-9.32)	0.77
Impaired fasting glucose	32 (25)	98 (75)	0.72
Hyperuricemia	20 (26)	57 (74)	0.93
Duration of renal replacement therapy	20.29 ± 21.66	23.61 ± 22.01	0.30
Total cholesterol (mmol/L)	4.27 ± 1.11	4.45 ± 1.17	0.28
LDL-cholesterol (mmol/L)	2.45 ± 0.93	2.77 ± 2.28	0.28
HDL-cholesterol (mmol/L)	1.35 ± 0.61	1.20 ± 0.44	0.08
Triglyceride (mmol/L)	1.46±0.95	1.66 ± 1.20	0.22
Mean phosphate level (mmol/L)	1.40 ± 0.46	1.59 ± 0.60	0.11	0.42 (0.18-1.08)	0.07
Family history of coronary artery disease	2 (10)	18 (90)	0.10	0.55 (0.08-3.64)	0.54
Pre-emptive transplant	1 (7)	13 (93)	0.26
Hemodialysis	55 (27)	152 (73)
Peritoneal dialysis	10(28)	26 (72)

AR: Aortic regurgitation; BMI: Body mass index; CI: Confidence interval; DD: Diastolic dysfunction; HD: Hemodialysis; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; LVH: Left ventricular hypertrophy; LVSD: Left ventricular systolic dysfunction; MR: Mitral regurgitation; OR: Odds ratio; PH: Pulmonary hypertension; PD: Peritoneal dialysis; TR: Tricuspid regurgitation.

Impact of LVH, LVSD, DD, and PH on eGFR

We compared the presence of LVH, LVSD, DD, and PH in KTRs with those who did not have these conditions and found no significant differences in eGFR up to two years of follow-up. Table 7 shows the impact of LVH, LVSD, DD, and PH on eGFR.

Table 7 Impact of left ventricular hypertrophy, left ventricular systolic dysfunction, diastolic dysfunction, and pulmonary hypertension on estimated glomerular filtration rates, mean ± SD.

Graft function	Echocardiographic findings				P value
eGFR	Number	mean ± SD	Number	mean ± SD
	LVH		No LVH
eGFR at discharge (mL/minute)	91	86.63 ± 30.37	164	91.40 ± 30.80	0.23
eGFR at 6 months (mL/minute)	90	86.40 ± 28.69	161	91.17 ± 29.10	0.21
eGFR at 1 year (mL/minute)	79	89.62 ± 25.62	136	91.60 ± 27.69	0.60
eGFR at 2 years (mL/minute)	51	86.73 ± 28.21	70	92.36 ± 25.47	0.25
	LVSD		No LVSD
eGFR at discharge (mL/minute)	31	83.97 ± 30.98	223	90.68 ± 30.55
eGFR at 6 months (mL/minute)	31	84.84 ± 30.78	219	90.26 ± 28.72
eGFR at 1 year (mL/minute)	23	92.26 ± 22.72	191	90.81 ± 27.45
eGFR at 2 years (mL/minute)	16	95.25 ± 24.92	105	89.18 ± 26.97
	DD		No DD
eGFR at discharge (mL/minute)	70	86.73 ± 32.56	185	90.82 ± 29.95	0.34
eGFR at 6 months (mL/minute)	70	87.56 ± 27.66	181	90.19 ± 29.53	0.52
eGFR at 1 year (mL/minute)	59	91.97 ± 26.45	156	90.46 ± 27.15	0.71
eGFR at 2 years (mL/minute)	34	93.03 ± 25.67	87	88.79 ± 27.13	0.43
	PH		No PH
eGFR at discharge (mL/minute)	66	90.97 ± 30.18	189	89.25 ± 30.91	0.70
eGFR at 6 months (mL/minute)	65	89.15 ± 26.46	186	89.56 ± 29.89	0.92
eGFR at 1 year (mL/minute)	63	91.05 ± 26.71	152	90.80 ± 27.07	0.95
eGFR at 2 years (mL/minute)	52	91.19 ± 26.72	69	89.07 ± 26.82	0.67

DD: Diastolic dysfunction; eGFR: Estimated glomerular filtration rate; LVH: Left ventricular hypertrophy; LVSD: Left ventricular systolic dysfunction; PH: Pulmonary hypertension.

DISCUSSION

A thorough cardiac evaluation before transplantation is crucial to ensure a better outcome. Initial cardiac screening may suggest suitability; however, even if suitability is established, echocardiographic assessment may still identify abnormalities that could impact post-transplant outcomes. An echocardiogram is, therefore, a crucial tool for assessing the heart's structural and functional status. This is the most comprehensive and detailed report on the predictors of LVH, LVSD, dilated cardiomyopathy (DCM), and PH from Saudi Arabia. In our cohort, we found LVH (64%), PH (25.5%), DD (27.5%), and LVSD (12%) in patients who successfully underwent transplantation. Similarly, a significant number of patients had MR, TR, and pericardial effusion.

All echocardiographic examinations were performed pre-transplant, approximately one month before surgery, and after dialysis sessions when patients were close to their target weight. This is to minimize the effect of volume overload on echocardiographic parameters, which can significantly alter chamber dimensions and function. Thus, our findings primarily reflect cardiac status under euvolemic conditions near the time of transplantation.

Uremia leads to myocyte hypertrophy, capillary loss, and interstitial fibrosis, reducing the capillary to myocyte ratio, ultimately leading to LVH[15]. We found LVH in 64%, which is comparable to the 65%-79% reported in other studies[16,17]. We found that male sex, PH, and dyslipidemia were significant predictors of LVH. Male gender has been reported in the literature as a risk factor for LVH. Myocardial mass is greater in males, and they are susceptible to pressure overload due to hormonal changes and higher baseline blood pressure[18], making them prone to develop LVH. Conversely, PH leads to right ventricular strain, which, through interventricular dependence, may lead to left ventricular remodeling and hypertrophy[19,20]. Elevated filling pressure and impaired myocardial relaxation in DD lead to chronic stress on the left ventricular wall, resulting in LVH[21]. This may also be a possible mechanism for LVH in our cohort. Dyslipidemia can also cause LVH through a variety of mechanisms. Potential pathogenic mechanisms include systemic inflammation, endothelial dysfunction, and accelerated atherosclerosis, which increase cardiac workload[21,22]. The interplay between male gender, PH, and dyslipidemia in the causation of LVH in CKD and transplant populations warrants further studies.

LVSD with ejection of < 50% has been reported in 13%-48% of ESRD studies[23-25]. We found LVSD in 12%, which is slightly lower than the reported studies, and may reflect a higher proportion of fit patients who were successful transplant candidates. LVSD is multifactorial in CKD and ESRD. This includes anemia, fluid overload, hypertension, and uremic toxins. Mineral and bone disorders, along with hyperphosphatemia, high fibroblast growth factor-23 levels, and reduced levels of Klotho, lead to abnormal myocardial remodeling, resulting in functional and structural abnormalities. Similarly, oxidative stress, endothelial dysfunction, and inflammation have been implicated in the development of heart failure[26]. In our cohort, we found DD and family history of coronary artery disease to be significant predictors of LVSD. The association of DD with LVSD suggests impaired relaxation and elevated filling pressures, leading to myocardial remodeling, fibrosis, and progressive loss of systolic function[20]. This could be a possible reason for DD in our cohort. The identification of a family history of coronary artery disease as a predictor of LVSD points to genetic and environmental predisposition, possibly through ischemia, myocardial fibrosis, and early-onset ventricular dysfunction in these patients. Family history is a well-documented risk factor for cardiovascular disease in the general population[27]. Further studies are needed to study the mechanism linking DD and the family history of coronary artery disease in the causation of LVSD in ESRD and transplantation.

We found DD in 27.5% of our cohort, which is much lower than the 49%-61% reported in the literature[28-30]. This may be due to the comparatively fit patients in our cohort who qualified for transplant and a short vintage of dialysis (22.65 ± 21.90 months), leading to a lower prevalence of DD. We found that peritoneal dialysis was a predictor of DD in our cohort. Although other factors, such as MR, LVH, and sudden death, showed a trend toward association, they did not achieve statistical significance in the multivariate analysis. Other studies re-enforced our findings, which found significantly higher DD in peritoneal dialysis patients[31,32]. A possible explanation is that chronic fluid shifts during peritoneal dialysis may lead to increased volume overload, ventricular remodeling, and impaired diastolic filling.

PH has been reported in 27%-56% in various studies[33-35]. We found PH in 25.5% of our cohort. Our cohort found LVH and grade 2-3 MR as independent risk factors for PH. MR with backward regurgitant flow is a well-known phenomenon that causes PH in the general population[35] and in patients with ESRD[36]. LVH has also been reported to be linked to the development of PH in ESRD[37,38]. The possible explanation for this LVH is that it leads to more left ventricular afterload, which in turn causes high left atrial pressure. The transmission of this pressure in the backward direction to the pulmonary circulation may contribute to PH.

Each of these conditions affects transplant outcomes. LVH has been shown to cause death and congestive heart failure after transplantation[39]. After renal transplant, the KTRs who had pre-transplant evidence of LVSD will have five times the cardiac mortality risk and two times the all-cause mortality risk of the general population[40]. Similarly, DD continues in half of the patients’ post-transplantation, and these patients[41] are prone to develop heart failure with preserved ejection fraction. PH has been associated with reduced patient survival[42].

We also found significantly high numbers of regurgitant valvular lesions and pericardial effusion in our cohort. We found MR in 86.8% of cases, although some were grade 1 (126, 56%). We found grade 2-3 MR in 45%. Different studies reported MR in 20%-64% of the ESRD patients[43-45]. Similarly, our cohort showed TR in 64.3% and AR in 17.4%. Volume overload, anemia, atrial and ventricular dilation, and hypertrophy might explain regurgitant murmurs in ESRD patients. We found mild to moderate pericardial effusion in 16.6% of the patients, which is comparable to the rates reported in the literature, ranging from 14.3% to 44%[46,47].

The impact of echocardiographic findings on graft function has been assessed by a few studies, yielding mixed results; however, most studies have not shown any effect on graft function. In a cohort of 30 KTRs followed for one year, it was found that patients with LVH had higher creatinine when compared to those without LVH[48]. On the other side, other studies found no effect on graft function. Kim et al[52] studied subclinical DD and found that subclinical DD can predict in-hospital major cardiovascular complications despite a reasonable eGFR, which increased gradually till day 7[49]. Another study from Canada found no significant difference in eGFR up to 6-month follow-up[50]. It was interesting to note that, despite the high prevalence of structural and functional cardiac abnormalities in our cohort, we found no significant association between LVH, LVSD, DD, or PH and graft function as measured by eGFR at discharge, 6 months, 1 year, and 2 years post-transplantation. Our study is unique in that it examines the effects of all possible echocardiographic abnormalities on eGFR, and significant patients undergo follow-up for up to two years. These findings are reassuring, and KTRs with echocardiographic abnormalities after appropriate evaluation can be transplanted with better graft function outcomes.

Successful transplantation may improve these abnormalities, including LVH, DD, and a reduction in the severity of valvular lesions[50,51]. Although kidney transplantation improves cardiovascular mortality, recipients of the renal allograft still have 10 times higher death rates than the general population[3]. Furthermore, cardiovascular disease is also the leading cause of death, with a functioning graft loss[4], it would be beneficial to look into these pre-transplant structural and functional abnormalities to identify factors and develop a pathway that could reduce future cardiovascular events and graft loss[52-55].

Our study has a few strengths and limitations. It is the largest cohort of pre-transplant echocardiography findings from Saudi Arabia, which reports in-depth structural and functional abnormalities in transplant candidates. Furthermore, it provides essential insights into predictors of LVH, DD, LVSD, and PH, as well as their impact on graft outcome. It regard to limitations, it is retrospective and may not have captured complete data. One potential source of bias in our study is that patients without an echo were excluded; thus, we could have missed patients with significant cardiac abnormalities. Lastly, being a single-center study, its findings cannot be generalized to other centers.

We recommend the following recommendations: We recommend a serial echocardiogram for surveillance to identify and monitor these cardiovascular abnormalities. We suggest implementing strategies for optimal blood pressure control, dyslipidemia management, and the appropriate use of immunosuppressive medications. We suggest treating these patients using a multidisciplinary approach via collaboration among the nephrologist, cardiologist, and transplant team. We suggest conducting prospective multicenter studies to investigate further and explore interventions targeting these predictors. We suggest further research on the use of sodium-glucose cotransporter 2 inhibitors and finerenone in patients with systolic and diastolic heart failure

CONCLUSION

Significant structural and functional cardiac abnormalities persist in potential KTRs, even after completing standard cardiac screening. Male sex, PH, DD, and dyslipidemia are independently associated with an increased risk of developing LVH. DD and a family history of coronary artery disease are key predictors of LVSD. Patients on peritoneal dialysis demonstrate a higher risk of developing DD. Additionally, KTRs with LVH and grade 2-3 MR show a greater propensity to develop PH. Notably, these cardiac abnormalities did not impact medium-term graft function. Future prospective studies are warranted to identify predictors, evaluate their influence on long-term cardiovascular and graft outcomes, and formulate strategies to enhance both patient and graft survival.