Left ventricular remodeling and its association with mineral and bone disorder in kidney transplant recipients

Abstract

Background

The assessment of left ventricular (LV) remodeling and its association with mineral and bone disorder (MBD) in kidney transplant recipients (KTRs) have not been systematically studied. We aimed to evaluate LV remodeling changes one year after kidney transplantation (KT) and identify their influencing factors.

Methods

Ninety-five KTRs (68 males; ages 40.2 ± 10.8 years) were followed before and one year after KT. Traditional risk factors and bone metabolism indicators were assessed. Left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF) and left ventricular diastolic dysfunction (LVDD) were measured using two-dimensional transthoracic echocardiography. The relationship between MBD and LV remodeling and the factors influencing LV remodeling were analyzed.

Results

One year after KT, MBD was partially improved, mainly characterized by hypercalcemia, hypophosphatemia, hyperparathyroidism, 25-(OH) vitamin D deficiency, elevated bone turnover markers, and bone loss. LVMI, the prevalence of left ventricular hypertrophy (LVH), and the prevalence of LVDD decreased, while LVEF increased. LVH was positively associated with postoperative intact parathyroid hormone (iPTH) and iPTH nonnormalization. ΔLVMI was positively associated with preoperative type-I collagen N-terminal peptide and postoperative iPTH. LVEF was negatively associated with postoperative phosphorous. ΔLVEF was negatively associated with postoperative iPTH. LVDD was positively associated with postoperative lumbar spine osteoporosis. Preoperative LVMI was negatively associated with ΔLVMI and positively associated with ΔLVEF. Advanced age, increased BMI, diabetes, longer dialysis time, lower albumin level, and higher total cholesterol and low-density lipoprotein levels were associated with LV remodeling.

Conclusions

LV remodeling partially improved after KT, showing a close relationship with MBD.

Keywords:

• Kidney transplantation
• mineral and bone disorder
• left ventricular remodeling
• left ventricular hypertrophy

Introduction

Cardiovascular disease accounts for over half of deaths in end-stage kidney disease (ESKD) [1], which is mainly due to heart failure and sudden cardiac death associated with uremic cardiomyopathy [2]. Left ventricular hypertrophy (LVH) is the cardinal feature of uremic cardiomyopathy, in addition to ventricular dilatation and both systolic and diastolic dysfunction. The gold standard for the treatment of ESKD is kidney transplantation (KT). The prevalence of cardiovascular complications remains high after KT, and cardiovascular events account for 36–55% of the causes of death in kidney transplant recipients (KTRs) [3]. The restoration of renal function associated with KT improves many factors that may cause uremic cardiomyopathy. However, whether kidney transplantation reduces left ventricular mass index (LVMI) and volumes and improves diastolic and systolic function is somewhat controversial [2,4].

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a nearly universal problem in patients with chronic kidney disease, which is only partially improved with transplantation. It will continue to manifest as abnormal bone metabolism, osteoporosis, and even fractures after KT, decreasing the survival rate of transplanted kidneys and recipients [5,6]. In chronic kidney disease (CKD) and KTRs, CKD-MBD has been shown to be associated with increased cardiovascular events [7]. For the non-CKD population, a close relationship has been observed between cardiovascular disease and osteoporosis [8]. Bone mineral density (BMD) has been demonstrated to be an independent determinant of LVMI in the general population [9,10].

However, relatively few studies have systematically investigated risk factors for left ventricular (LV) remodeling changes and evaluated the association between bone disease and LV remodeling in the posttransplant setting. In this study, KTRs in our center were followed for mineral and bone disorder (MBD) and LV remodeling before and one year after KT. We analyzed the possible influencing factors of LV remodeling and evaluated the relationship between MBD and LV indices to explore the effect of bone disease on LV remodeling, as well as to provide directions for the comprehensive assessment and prevention of cardiovascular events in KTRs.

Materials and methods

1. Patients and study design

Patients in this study were derived from our previous prospective cohort study [11], which followed up 95 patients receiving their first KT allograft in our center for one year. This study was approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (Ethics Number 2016-SR-029). All the patients signed an informed consent form before participating in the study.

For the inclusion and exclusion criteria, please refer to the previously reported study [11].

Data on clinical information, laboratory examinations, and imaging examinations were collected within three months before and one year after KT under the same detection conditions.

2. Clinical data

Data collected from the KTRs included sex, age, body mass index (BMI), menstrual status, dialysis method and dialysis time, primary kidney disease, hypertension, diabetes, smoking history (continuous or cumulative smoking for 6 months or longer), drinking history (daily alcohol intake of ≥ 3 units, the unit referring to the WHO fracture risk assessment system), history of total parathyroidectomy with forearm autotransplantation (TPTX + AT), blood pressure at the point of follow-up, use of immunosuppressants, use of calcium, calcitriol, cinacalcet, anti-hypertension drugs and statins.

For the immunosuppressive regimen, please refer to the previously reported study [11].

3. Laboratory measurements

Fasting blood samples from all the included KTRs were collected in the morning. A Sysmex XN9000 hematology analyzer was used to measure blood routine examination. A Cobas e602 automatic electrochemical luminescence analyzer (Roche, Basel, Switzerland) was used to measure Scr, uric acid, total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), albumin, calcium (Ca), phosphorus, 25-hydroxyvitamin D(25(OH)vitD), intact parathyroid hormone (iPTH), bone-specific alkaline phosphatase (BALP), and osteocalcin (OC). A Cobas e170 automatic electrochemical luminescence analyzer (Roche, Basel, Switzerland) was used to measure the Type I collagen cross-linked N-terminal peptide (NTx) and type I collagen cross-linked C-terminal peptide (CTx). Corrected Ca levels were calculated using the following formula: Correction Ca = serum Ca + (40-serum Alb) ×0.02. The serum Ca levels in the following text were corrected. iPTH unnormalization was defined as iPTH level not decreasing to the normal reference range(≤88pg/mL).

Estimated glomerular filtration rate (eGFR) was calculated using the MDRD formula. CKD stages were evaluated according to ‘Guidelines for Quality of Life of Kidney Diseases and Dialysis Patients’ (Kidney Disease Outcomes Quality Initiative, K/DOQI): CKD 1 T GFR ≥ 90 mL/(min × 1.73 m²), CKD 2 T GFR 60–89 mL/(min × 1.73 m²), CKD 3 T eGFR 30–59 mL/(min × 1.73 m²), CKD 4 T eGFR 15–29 (ml/(min × 1.73 m²), and CKD 5 T eGFR < 15 mL/(min × 1.73 m²).

4. Parathyroid hyperplasia and bone mineral density (BMD)

A GE Logiq E9 Ultrasound Diagnostic Device (GE Healthcare, Milwaukee, WI, USA) was used to evaluate parathyroid hyperplasia.

Dual-energy X-ray absorptiometry (DEXA) (Discovery W S/N 85065; Hologic, 35 CrosbyDrive BedFord, USA) was used to determine the BMD of the femoral neck and vertebra. Bone density was expressed in terms of area g/cm². Diagnostic criteria for osteoporosis refered to WHO standards [12].

5. Left ventricular structure and function

Two-dimensional transthoracic echocardiography was performed in all participants. Measurements included ascending aorta diameter(Aod), left atrial diameter(LAD), left ventricular end-diastolic diameter(LVDd), left ventricular end-systolic diameter(LVDs), interventricular septal thickness(IVS), posterior left ventricular wall thickness(LVPW), left ventricular ejection fraction (LVEF), mitral valve diastolic flow velocity (E1, A1), mitral ring lateral wall and septal motion velocity (E ‘). The left ventricular mass (LVM) and LVMI were calculated according to the formula of Devereux and Reichek [13]. LVH was defined as LVMI ≥47 g/m^2.7 in females and ≥ 50 g/m^2.7 in males. LV systolic dysfunction was defined as LVEF< 50%. Left ventricular diastolic dysfunction(LVDD) was defined as E-wave/A-wave < 1, septal e’<7 and lateral wall e’<10.

6. Statistical analysis

The SPSS software (version 25.0) was used for data processing. Normally distributed continuous variables were expressed as mean ± standard deviation ($x$±s), and paired comparisons between baseline and follow-up indicators were performed using a paired t-test. Non-normally dis­tributed continuous variables are expressed as medians (P25-P75), and paired comparisons between baseline and follow-up indicators were performed using the Wilcoxon signed-rank test. Categorical variables are expressed as rate or composition ratio % (frequency). The Pearson correlation test or Spearman correlation test was used for correlation analysis between bone metabolism indicators and LV index. To explore the factors influencing LV remodeling, if the dependent variable was a continuous variable with a normal distribution, univariate and multivariate linear regression analyses were used; if the dependent variable was a continuous variable with a non-normal distribution, the logarithm of the dependent variable was used for linear regression analysis, and if the dependent variable was a binary classification variable, univariate and multivariate binary logistic regression analyses were used. The index whose difference was statistically significant in univariate analyses was inlcuded in the multivariate analyses, and multicollinearity were checked in the multivariate mode. Factors related to hypertension, diabetes, hyperlipidemia, hyperuricemia, hemo­globin, albumin, bone metabolism index and appropriate medication informations had all been evaluated in the analysis of influencing factors of LV remodeling. We only displayed the measures with statistically significant differences. Two-sided p < 0.05 indicated a statistically significant difference.

Results

1. Clinical data of KTRs

Basic clinical data of the 95 KTRs are shown in Table 1. None of the recipients received cinacalcet before or after the KT. Change of relevant clinical and laboratory index after KT were displayed in Table 2. Prevalence of hypertension and anti-hypertension drug usage decreased, while serum hemoglobin increased.

Table 1. Basic clinical data of enrolled KTRs (n = 95).

Index	Level	n = 95
Age(years)		40.2 ± 10.8
Sex, %(N)	Male	71.6(68)
	Female	28.4(27)
Menstrual status, %(N)	Premenopausal	24.2(23)
	Menopausal	4.2(4)
Time of RRT(months)		27(14,48)
Dialysis mode, %(N)
	Hemodialysis	70.5 (67)
	Peritoneal dialysis	29.5 (28)
Primary kidney disease, %(N)
	Glomerulonephritis	93.7(89)
	Anaphylactic purpura nephritis	3.2(3)
	Polycystic kidney	2.1(2)
	Interstitial nephritis	1.1(1)
Smoking, %(N)		7.4(7)
Alcohol taking, %(N)		5.3(5)
TPTX + AT, %(N)		4.2(4)
Pre-parathyroid hyperplasia/nodule, %(N)		23.1(22)
Post-parathyroid hyperplasia/nodule, %(N)		28.4(27)
Post-erythropoietin, %(N)		6.3(6)
Post-statins, %(N)		9.5(9)
Post-calcium use, %(N)		6.3(6)
Post-calcitriol use, %(N)		20.0(19)
Post-eGFR (mL/min *1.73 m^2)		74.7 ± 21.3
CKD stage one year post-KT, %(N)
	CKD 1 T	25.3(24)
	CKD 2 T	49.5(47)
	CKD 3 T	25.3(24)
	CKD 4 T	0(0)
	CKD 5 T	0(0)

Abbreviations: KTRs: kidney transplant recipients; RRT: Renal replacement therapy; TPTX + AT: total parathyroidectomy with forearm autotransplantation; eGFR: estimated glomerular filtration rate; CKD: chronic kidney disease; KT: kidney transplantation.

Table 2. Change of relevant clinical and laboratory index after KT.

Index	Pre-transplantation	Post-transplantation	p-value
BMI (kg/m^2)	21.2 ± 3.3	21.7 ± 4.0	0.877
Hypertension, %(N)	82.1(78)	57.9(55)	<0.001
Diabetes, %(N)	9.5(9)	12.6(12)	0.180
CCB, %(N)	62.1(59)	42.1(40)	0.001
ACEI/ARB, %(N)	30.5(29)	11.6(11)	<0.001
SBP(mmHg)	144.4 ± 17.6	128.6 ± 15.0	<0.001
DBP(mmHg)	92.1 ± 14.6	80.9 ± 10.9	<0.001
Hemoglobin(g/L)	112.60 ± 20.05	135.12 ± 21.45	<0.001
Albumin(ng/ml)	41.94 ± 5.5	40.82 ± 3.18	0.066
Uric Acid(μmmol/L)	378.35 ± 118.32	348.79 ± 78.78	0.048
TC(mmol/L)	4.47 ± 1.17	4.65 ± 0.98	0.245
TG(mmol/L)	1.89 ± 1.47	1.42 ± 0.76	0.002
HDL(mmol/L)	1.08 ± 0.54	1.26 ± 0.28	0.001
LDL(mmol/L)	2.89 ± 0.74	2.80 ± 0.64	0.334

Abbreviations: KT, Kidney transplantation; BMI, body mass index; CCB, calcium channel blockers; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

2. Changes in bone metabolism biochemical markers and BMD in KTRs

One year after KT, serum P, iPTH, OC, NTx, CTx, femoral neck (FN) BMD and lumbar spine (LS) BMD decreased (p < 0.05), while 25-(OH) vitamin D levels remained low before and after KT (Table 3). The prevalence of bone loss increased significantly (p < 0.05) (Figure 1).

Figure 1. Prevalence of osteopenia and osteoporosis (%) at various skeletal sites (FN, femoral neck; LS, lumbar spine).

Table 3. Changes of metabolism biochemical markers and BMD after KT (n = 95).

Index	Pre-transplantation	Post-transplantation	P-value
Ca(mmol/L)	2.33 ± 0.23	2.37 ± 0.15	0.136
P(mmol/L)	1.85 ± 0.55	0.93 ± 0.18	<0.001
iPTH (pg/mL)	347.21 ± 306.22	100.66 ± 70.33	<0.001
25(OH)vitD(nmol/L)	47.38 ± 29.06	45.70 ± 18.02	0.527
OC(ng/mL)	180.83 ± 100.27	25.74 ± 20.69	<0.001
BALP(U/L)	17.67 ± 13.54	19.09 ± 14.60	0.342
NTx(ng/ml)	319.12 ± 301.32	76.25 ± 79.14	<0.001
CTx(ng/ml)	2.21 ± 1.40	0.76 ± 0.52	<0.001
FN BMD (g/cm^2)	0.75 ± 0.13	0.69 ± 0.09	0.001
LS BMD (g/cm^2)	0.97 ± 0.11	0.87 ± 0.28	0.021

Abbreviations: BMD: bone mineral density; LV: left ventricular; KT: kidney transplantation; Ca: calcium; P: phosphorus; iPTH: intact parathyroid hormone; 25(OH)vitD: 25-hydroxyvitamin D; OC: osteocalcin; BALP: bone specific alkaline phosphatase; NTx: Type I collagen cross-linked N-terminal peptide; CTx: Type I collagen cross-linked C-terminal peptide; FN BMD: femoral neck bone mineral density; LS BMD: lumbar spine bone mineral density.

3. Changes of LV index in KTRs

One year after KT, LVMI, the prevalence of LVH, and the prevalence of LVDD decreased, while the levels of LVEF were elevated (Table 4). ΔLVMI and ΔLVEF were −7.70 ± 20.17g/m^2.7 and 3.08 ± 9.69%. Other cardiac ultrasound index were displayed in Table 4.

Table 4. Changes of LV index after KT (n = 95).

Index	Pre-transplantation	Post-transplantation	p-value
LVMI(g/m^2.7)	60.00 ± 19.43	51.42 ± 13.23	0.001
LVH, %(N)	57.9(55)	42.1(40)	0.004
LVEF(%)	62.06 ± 5.34	64.06 ± 2.42	0.005
LVDD, %(N)	21.4(20)	9.5(9)	0.038
Aod(mm)	29.20 ± 3.20	29.56 ± 3.12	0.334
LAD(mm)	35.40 ± 5.67	34.00 ± 4.65	0.025
LVDd(mm)	49.09 ± 5.98	46.43 ± 3.90	<0.001
LVDs(mm)	32.84 ± 4.83	30.25 ± 2.59	<0.001
IVS(mm)	11.38 ± 2.75	10.85 ± 1.30	0.079
LVPW(mm)	10.85 ± 1.68	10.48 ± 1.21	0.039
FS(%)	33.56 ± 3.91	34.85 ± 1.82	0.014
E1(cm/s)	75.32 ± 20.18	66.60 ± 15.73	0.001
A1(cm/s)	80.54 ± 17.53	75.52 ± 18.29	0.033
septal motion E’(cm/s)	7.05 ± 2.28	7.80 ± 5.04	0.234
mitral ring lateral wall E’(cm/s)	9.91 ± 0.29	0.93 ± 0.31	0.104
E/A	0.97 ± 0.29	0.93 ± 0.31	0.252
E/e’	9.53 ± 2.98	9.77 ± 2.18	0.867

Abbreviations: LVMI: left ventricular mass index; LVH: left ventricular hypertrophy; LVEF: left ventricular ejection fraction; LVDD: left ventricular diastolic dysfunction; Aod: ascending aorta diameter; LAD: left atrial diameter; LVDd: left ventricular end-diastolic diameter; LVDs: left ventricular end-systolic diameter; IVS: interventricular septal thickness; LVPW: posterior left ventricular wall thickness; LVEF: left ventricular ejection fraction; E1, A1: mitral valve diastolic flow velocity; E ‘: mitral ring lateral wall and septal motion velocity.

Table 5. Results of logistic regression analysis of influencing factors of postoperative LVH (n = 95).

Factors	Univariate analysis			Multivariate analysis
	OR	95%CI	p-value	OR	95%CI	p-value
Age(years)	1.067	1.021 ∼ 1.115	0.004
pre-BMI (kg/m^2)	1.370	1.135 ∼ 1.653	0.001	1.268	1.023 ∼ 1.570	0.030
post- iPTH (pg/mL)	1.007	1.000 ∼ 1.015	0.048
iPTH unnormalization	5.633	2.073 ∼ 15.311	0.001	5.030	1.099 ∼ 23.014	0.037

Abbreviations: LVH: left ventricular hypertrophy; BMI: body mass index; P: phosphorus; iPTH: intact parathyroid hormone.

Annotation: All demographic and biochemical variables have been tested, including factors related to hypertension, diabetes, hyperlipidemia, hyperuricemia, hemoglobin, albumin, bone metabolism index and appropriate medication informations, and only significant factors were included in the table.

4. Relationship between LV remodeling and bone metabolism indicators in KTRs

Postoperative LVMI was positively correlated with postoperative iPTH (r = 0.350, p = 0.001). ΔLVMI was positively correlated with postoperative iPTH (r = 0.265, p = 0.017) and preoperative NTx (r = 0.238, p = 0.039).

The postoperative LVEF was negatively correlated with the postoperative phosphorus level (r= −0.255, p = 0.015). ΔLVEF was negatively correlated with postoperative iPTH (r= −0.310, p = 0.005).

5. Factors influencing LV remodeling in KTRs

5.1. Influencing factors of LVH in KTRs

Univariate binary logistic regression analysis showed that postoperative LVH was positively associated with age, preoperative BMI, postoperative iPTH, and iPTH nonnormalization. The associations with BMI and iPTH nonnormalization were still statistically significant in multivariate analysis (Table 5, all demographic and biochemical variables tested, and only significant factors included in the table).

Univariate linear regression analysis showed that ΔLVMI was positively associated with dialysis time, preoperative NTx, postoperative BMI, and postoperative iPTH and negatively associated with preoperative LVMI. The associations with preoperative LVMI and postoperative iPTH were still statistically significant in multivariate analysis (Table 6; all demographic and biochemical variables tested, but only the significant factors, are included in the table).

Table 6. Results of linear regression analysis of influencing factors of ΔLVMI (n = 95).

Factors	Univariate analysis			Multivariate analysis
	Regression coefficient	95%CI	p-value	Regression coefficient	95%CI	p-value
Time of RRT(months)	0.226	0.065 ∼ 0.386	0.007
pre-NTx(ng/ml)	0.017	0.003 ∼ 0.031	0.018
pre-LVMI(g/m^2.7)	−0.778	−0.922∼-0.634	<0.001	−0.697	−0.814∼-0.579	<0.001
post-BMI (kg/m^2)	1.55	0.535 ∼ 2.564	0.003
post- iPTH (pg/mL)	18.581	1.082 ∼ 36.08	0.038	15.034	4.498 ∼ 25.569	0.006

Abbreviations: ΔLVMI: change of left ventricular mass index; RRT: Renal replacement therapy; Mg: magnesium; NTx: Type I collagen cross-linked N-terminal peptide; LVMI: left ventricular mass index; BMI: body mass index; iPTH, intact parathyroid hormone.

Annotation: All demographic and biochemical variables have been tested, including factors related to hypertension, diabetes, hyperlipidemia, hyperuricemia, hemoglobin, albumin, bone metabolism index and appropriate medication informations, and only significant factors were included in the table.

5.2. Influencing factors of LVEF in KTRs

Univariate linear regression analysis showed that postoperative LVEF was negatively associated with postoperative phosphorus and ΔLVMI, and the associations were still statistically significant in multivariate analysis (Table 7, all demographic and biochemical variables tested, and only significant factors included in the table).

Table 7. Results of linear regression analysis of influencing factors of postoperative LVEF (n = 95).

Factors	Univariate analysis			Multivariate analysis
	Regression coefficient	95%CI	p-value	Regression coefficient	95%CI	p-value
post- P(mmol/L)	−0.050	−0.087∼-0.012	0.011	−0.052	−0.090∼-0.013	0.009
ΔLVMI(g/m^2.7)	−0.00038	−0.00075∼-0.00003	0.037	−0.000425	−0.000768∼-0.000083	0.015

Abbreviations: LVEF: left ventricular ejection fraction; P: phosphorus; Δ LVMI: change of left ventricular mass index.

Annotation: All demographic and biochemical variables have been tested, including factors related to hypertension, diabetes, hyperlipidemia, hyperuricemia, hemoglobin, albumin, bone metabolism index and appropriate medication informations, and only significant factors were included in the table.

Univariate linear regression analysis showed that ΔLVEF was positively associated with preoperative albumin, preoperative LVMI, and postoperative albumin and negatively associated with age, preoperative BMI, preoperative LVEF, and postoperative iPTH. The associations with preoperative BMI and preoperative LVEF were still statistically significant in multivariate analysis (Table 8; all demographic and biochemical variables tested, but only the significant factors, are included in the table).

Table 8. Results of linear regression analysis of influencing factors of ΔLVEF (n = 95).

Factors	Univariate analysis			Multivariate analysis
	Regression coefficient	95%CI	p-value	Regression coefficient	95%CI	p-value
Age(years)	−0.241	−0.428∼−0.055	0.012
pre-BMI (kg/m^2)	−0.545	−1.069∼−0.022	0.041	−0.24	−0.422∼−0.025	0.011
pre-albumin(g/L)	0.48	0.105 ∼ 0.855	0.013
pre-LVEF(%)	−1.08	−1.18∼−0.98	<0.001	−1.152	−1.291∼−1.013	<0.001
pre-LVMI(g/m^2.7)	0.148	0.084 ∼ 0.212	<0.001
post-albumin(g/L)	1.059	0.419 ∼ 1.698	0.001
post-iPTH (pg/mL)	−0.036	−0.065∼−0.006	0.019

Abbreviations: ΔLVEF: change of left ventricular ejection fraction; BMI: body mass index; Alb: albumin; LVEF: left ventricular ejection fraction; LVMI: left ventricular mass index; iPTH: intact parathyroid hormone.

Annotation: All demographic and biochemical variables have been tested, including factors related to hypertension, diabetes, hyperlipidemia, hyperuricemia, hemoglobin, albumin, bone metabolism index and appropriate medication informations, and only significant factors were included in the table.

Table 9. Results of logistic regression analysis of influencing factors of postoperative LV diastolic dysfunction (n = 95).

Factors	Univariate analysis			Multivariate analysis
	OR	95%CI	p-value	OR	95%CI	p-value
Age(years)	1.130	1.037 ∼ 1.231	0.005	1.119	1.009 ∼ 1.241	0.033
pre-diabetes	7.700	1.471 ∼ 40.293	0.016
post-diabetes	8.571	1.863 ∼ 39.426	0.006
post-TC(mmol/L)	2.092	1.007 ∼ 4.346	0.048
post-LDL(mmol/L)	2.964	1.051 ∼ 8.358	0.040
pre-uric acid	0993	0.987 ∼ 0.999	0.028	0.989	0.979 ∼ 0.998	0.019
post-LS BMD
Osteopenia^a	2.120	0.399 ∼ 11.256	0.378	2.742	0.376 ∼ 19.994	0.320
Osteoporosis^a	17.667	1.809 ∼ 172.571	0.014	39.331	1.775 ∼ 871.569	0.020

Abbreviations: LV: left ventricular; TC: total cholesterol; LDL: low-density lipoprotein; LS BMD: lumbar spine bone mineral density.

^a Compared with the group with normal BMD level.

Annotation: All demographic and biochemical variables have been tested, including factors related to hypertension, diabetes, hyperlipidemia, hyperuricemia, hemoglobin, albumin, bone metabolism index and appropriate medication informations, and only significant factors were included in the table.

5.3. Influencing factors of LV diastolic dysfunction in KTRs

Univariate binary logistic regression analysis showed that postoperative LV diastolic dysfunction was positively associated with age, preoperative diabetes, postoperative diabetes, postoperative TC, postoperative LDL, preoperative uric acid and postoperative LS osteoporosis. The associations with age, preoperative uric acid and LS osteoporosis were still statistically significant in multivariate analysis (Table 9; all demographic and biochemical variables tested, but only the significant factors, were included in the table).

Discussion

After KT, mineral and bone disorder will only be partially improved as transplanted kidney function recovers. As a result, a considerable number of kidney transplant recipients are afflicted with abnormal bone metabolism, osteoporosis, and even fracture, which are associated with increased cardiovascular events and decreased survival rates of transplanted kidneys and recipients. Our data indicated that MBD after KT manifested as an increased prevalence of hypophosphatemia and bone loss, persistent 25-(OH) vitamin D deficiency and partially decreased iPTH and bone turnover markers, which was consistent with other studies [14,15].

The annual risk of cardiovascular events in KTRs was reported to be 3.5–5%, and cardiovascular events accounted for 36–55% of the cause of death in KTRs [3]. Patients with end-stage kidney disease have a high prevalence of LVH, which cannot be completely relieved after KT. Studies have shown that KTRs have a higher mortality rate from cardiovascular disease than the general population, and LVH is associated with graft function and the course of cardiovascular disease in KTRs [16]. In our study, the data showed that one year after KT, the prevalence of LVH decreased (from 58% to 42%), and left ventricular systolic and diastolic function improved. Other studies have also shown that LVH could improve with the improvement of graft function; however, 12 months after surgery, 65% of nondiabetic recipients still had LVH [17]. Džemidžić et al. [18] reported that the proportion of patients with LVH reduced dramatically from 67% to 37% after kidney transplantation, which was consistent with our result. Montanaro et al. [19] shown that the prevalence of LVH significantly decreased (78% versus 44%, p < 0 .03) after 2 years of kidney transplantation. ΔLVMI in our study was −7.70 ± 20.17g/m^2.7. In Vaidya’s study [20], 57 of 105 patients had significant LV mass regression (mean difference −37.2 ± 31.3 g/m²), while the other 48 had no significant regression (mean difference 15.7 ± 17.1 g/m²). Sandeep et al. [21] showed that six months after KT, the LVMI was significantly reduced in the recipients(124.8 ± 39 vs. 102.2 ± 24.4 g/m², p < 0.001), while the LVEF was significantly increased(57.8 ± 7 vs. 60.1 ± 1.9, p = 0.015), which was consistent with our result(LVEF was elevated from 62.06 ± 5.34% to 64.06 ± 2.42%). Prasad et al. [22] used cardiac magnetic resonance to evaluate LV remodeling and reported that LV end-systolic volume and LV end-diastolic volume but not LVMI or LVEF improved post-KT. One study assessed cardiac function in patients before and three months after KT and showed significant improvement in LVEF and a reduction in chamber diameter [23]. Jasminka et al. [24] reported that one year after KT, the prevalence of left ventricular diastolic function decreased from 56% to 40%. In our study, our patients had better baseline left ventricular diastolic function, and the prevalence of LVDD decreased from 21.4% to 9.5% one-year post-KT. However, some degree of LVH is usually still present in KTRs and may worsen as the function of the transplanted kidney declines [20,25].

Mineral and bone disorder has been shown to play a role in the development of LVMI in KTRs. Our study demonstrated that one year after KT, LVH and ΔLVMI were positively associated with postoperative iPTH, while ΔLVEF was negatively associated with postoperative iPTH. LVH was positively associated with iPTH nonnormalization. LVEF was negatively associated with postoperative phosphorus. In a cross-sectional study, Saleh et al. [26] found that PTH was an independent predictor of LVH in patients with end-stage renal disease [27]. Treatment of secondary hyperparathyroidism with paricalcitol has a beneficial effect on LVH remission [28]. This may be because PTH promotes myocardial hypertrophy, uncoordinated myocardial contraction, and impaired relaxation by inhibiting the metabolism of long-chain and short-chain fatty acids in cardiomyocytes and activating the renin-angiotensin-aldosterone system [29]. Hyperphosphatemia has cardiac effects independent of PTH, stimulating the transformation of vascular smooth muscle cells into osteoblasts with mineralized precursors, which in turn cause arterial calcification and increased cardiac afterload in this setting. In the short term after kidney transplantation, the recipient’s FGF-23 remained high, which regulates urinary phosphorus excretion. Wolf et al. [30] reported that high FGF23 levels were associated with cardiovascular disease, mortality and CKD progression after transplantation, which may be related to FGF23-mediated inhibition of active vitamin D synthesis and phosphorus excretion. Faul et al. [31] also demonstrated a direct correlation between high FGF23 levels and LVH, and proved that FGF23 administration could induce LVH in mice. The authors further confirmed that the administration of anti-FGF receptor antibodies can reduce LVH, suggesting that FGF23 may directly cause cardiac damage. In this study, the effect of FGF23 on postoperative LV remodeling was not assessed because FGF23 levels were not detected. However, our study suggested the effect of persistent hyperparathyroidism after KT on left ventricular remodeling and function, which prompted active control of hyperparathyroidism in KTRs.

Our study also found that ΔLVMI was positively asso­ciated with preoperative NTx and that LV diastolic dysfunction was associated with postoperative LS osteoporosis. Epidemiological studies [8] also showed that osteoporosis and osteopenia were risk factors for cardiovascular disease or atherosclerosis disease. In the general female population and older men, BMD was shown to be an independent factor determining LVMI [9,10]. In the study by Hisashi et al. [32], decreased BMD in hypertensive patients was associated with LV diastolic dysfunction. In patients with primary hyperparathyroidism, high levels of bone formation markers were observed to be independently associated with better left ventricular diastolic and systolic function [33]. The mechanism of osteoporosis and left ventricular remodeling and dysfunction may be related to lipid oxidation, vitamin D deficiency, hyperparathyroidism and the high expression of some inflammatory factors. These factors can directly accelerate atherosclerosis, stimulate osteoclast activity, and promote bone resorption [34].

We also found that preoperative LVMI was negatively associated with ΔLVMI and positively associated with ΔLVEF, indicating that patients with higher pre-LVMI had more structural and functional recovery one year after KT. In Prasad’s study, the LVMI declined the most in ESKD patients with the highest pre-KT LVMI, which was consistent with our study [22]. Hernández et al. demonstrated that predialysis LVMI may perpetuate cardiac growth following KT [35]. We hypothesized that the different results may be attributed to the different severity degrees of pretransplant left ventricular remodeling in the study population.

In addition, in our study, advanced age, increased BMI, diabetes, longer dialysis time, lower albumin level, higher uric acid level and higher TC and LDL levels were associated with LV remodeling, which was in accordance with other studies [35–37]. Thus, active control of hyperglycemia, hyperlipemia and hyperuricemia, keeping BMI in the appropriate range, increased intake of high-quality protein, and shortening pre-KT dialysis time may help improve left ventricular function.

This study is a prospectively designed follow-up study. The strengths of this study are as follows: first, the relationship between bone metabolism indicators and LV remodeling was evaluated extensively; second, the factors influencing LV remodeling were analyzed comprehensively. There also exist some limitations. First, the relatively small sample size and one-year follow-up time is one of the limitations, which limited the identification of risk factors for LV remodeling and the generalization of the results to other transplant centers. Second, Echocardiography was performed by different people. Thus, the detection results may have inter-individual variability. Third, FGF23 levels were not detected and the effect of FGF23 on postoperative LV remodeling was not assessed. Moreover, most recipients were of CKD1T-3T stage, and therefore the results could not be generalized to KTRs of CKD4T-5T stage.

In conclusion, one year after KT, mineral and bone disorder persisted, and left ventricular structural and functional abnormalities were partially improved. In addition to traditional risk factors, left ventricular remodeling was strongly associated with mineral and bone disorder. The higher the preoperative iPTH, serum phosphorus, and bone loss were, the more serious the LV remodeling was. Patients with higher pre-LVMI had more structural and functional recovery one year after KT. Active control of risk factors such as MBD, hyperglycemia and hyperlipemia, shortening pre-KT dialysis time and increased intake of high-quality protein may help decrease cardiovascular complications and improve the long-term survival rate of KTRs.

Acknowledgment

We acknowledged that patients in this study were derived from our previous prospective cohort study(Sun, L., Wang, Z., Zheng, M., Hang, Z., Liu, J., Gao, X., Gui, Z., Feng, D., Zhang, D., Han, Q., Fei, S., Chen, H., Tao, J., Han, Z., Ju, X., Gu, M., & Tan, R. (2023). Mineral and bone disorder after kidney transplantation: a single-center cohort study. Renal Failure, 45(1), 2210231).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Reasonable requests for data will be accommodated by contacting the corresponding author.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [grant numbers 82270790, 82170769, 82070769, 81900684, 81870512], the ‘333 High Level Talents Project’ in Jiangsu Province [grant numbers BRA2015469, BRA2016514], Jiangsu Province Natural Science Foundation Program [grant number BK20191063] and Jiangsu Province Capability Improvement Project through Science, Technology and Education [grant number ZDXK202219].