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Introduction

Kidney transplantation is a treatment option for end-stage renal disease patients, which has several benefits for the patients, such as a higher quality of life, lower costs, and fewer dietary restrictions, amongst others (1-3). However, this surgery carries the risks of post-transplant complications, including delayed graft function, vascular calcification, bone fractures, diabetes, and infection, amongst other issues (4-8). These complications threaten the success of a graft and may further lead to the death of patients who received kidney transplantation (9-11). Therefore, exploring therapeutic approaches that reduce the occurrence of these post-transplant complications is crucial to improve the clinical outcomes of patients receiving kidney transplantation.

Vitamin K is a hydrophobic vitamin that serves as a cofactor of the enzyme γ-glutamyl carboxylase to activate several vitamin K-dependent proteins, thereby improving vascular and bone health (12). Recently, several studies have explored the effect of vitamin K on improving clinical outcomes (such as renal function, vascular calcification, and all-cause mortality) in patients receiving kidney transplantation (13-20); however, these findings are contested. For example, one previous study found that a higher vitamin K status was related to increased renal function in patients receiving kidney transplantation (20). Additionally, vitamin K sufficiency is correlated with lower all-cause mortality in these patients (15). However, another study found that vitamin K supplementation did not reduce vascular stiffness, vascular calcification, or renal function in patients receiving kidney transplantation, which indicated that vitamin K supplementation had no influence on improving the clinical outcomes of these patients (19). As a result, whether vitamin K improves clinical outcomes in patients receiving kidney transplantation should be further explored.

Accordingly, this meta-analysis was performed to explore the correlation of vitamin K status with all-cause mortality, renal function, inflammation, as well as vascular and bone health in patients receiving kidney transplantation.

Materials and methods

Search strategy

Electronic databases (EMBASE, PubMed, and Cochrane) were used to screen the papers relating to the effects of vitamin K status on clinical outcomes of patients who received kidney transplantation from conception to December 2022. Key words and medical subject headings were applied, including ‘vitamin K’, ‘VK’, ‘vitamin-K’, ‘V-K’, ‘kidney transplant’, ‘renal transplant’, ‘kidney transplantation’, ‘renal transplantation’, ‘kidney graft’, and ‘renal graft’.

Eligibility criteria

Inclusion criteria for study screening were: i) Patients >18 years old; ii) patients received a kidney transplant; iii) studies assessed the impact of vitamin K status or vitamin K supplementation on clinical outcomes after kidney transplantation; iv) studies involved at least one clinical outcomes of interest to the present study; and v) published in English. The exclusion criteria were: i) Reviews, case reports, or letters; or ii) had no available data for extraction.

The clinical outcomes of interest in the present study were: i) All-cause mortality; ii) renal function indexes; iii) and C-reactive protein (CRP).

Study selection

In the present meta-analysis, two reviewers independently completed the study screening. In brief, the titles and abstracts were assessed for preliminary screening. Then, the full texts which met the inclusion criteria were downloaded and assessed. The studies which met the exclusion criteria were ineligible for inclusion, and the excluded cause was recorded. Additionally, the relevant publications lists were also identified. Any disagreements were resolved by conversation and reaching a consensus. For studies with overlapping populations, those with a larger population or a longer follow-up period were included.

Data collection and risk of bias

Two reviewers independently finished the data collection and assessment of bias risk. The disagreements were resolved by consensus. The extracted data included authors' names, publication year, study design, demographic information of patients, and outcomes. The Newcastle-Ottawa Scale criteria were utilized to assess the risk of bias, involving 3 domains: Selection, comparability, and outcome (21). The risk of bias in the included studies was classified as low risk (score, >8), medium risk (score, 5-7), or high risk (score, ≤4).

Statistical analysis

The analyses were completed per the Preferred Reporting Item for Systematic Reviews and Meta-analyses (PRISMA) using Stata (version 14.0, StataCorp LP). In the present meta-analysis, normal vitamin K status or vitamin K supplementation was considered as the experimental group; while vitamin K deficiency or no vitamin K supplementation was considered as the control group. Relative risk (RR) with 95% confidence intervals (CIs) was used for dichotomous outcomes, and mean difference (MD) with 95% CI was used for continuous outcomes. The heterogeneity was determined using I2 statistics: If I2≤50.0% and/or P≥0.05, the heterogeneity was considered insignificant, and the fixed effects model was used; otherwise, the random effects model was used (22). The sensitivity analysis was performed by omitting each study and then repeating the analysis. Egger's and Begg's tests were utilized to evaluate publication bias and P<0.05 was considered to indicate a statistically significant difference. R version 3.6 and R studio version 4.2.2 were utilized for analyses (23,24).

Results

Study screening procedure

A total of 393 records were identified through searching of databases, including 161 records from EMBASE, 187 records from PubMed, and 45 records from Cochrane, of which 108 records were excluded as duplicates, leaving 285 records to be screened. A further 264 records were excluded after screening of the titles and abstracts, including 172 reviews or meta-analyses, 89 irrelevant studies, and 3 case reports. Subsequently, 21 full-text records were assessed for eligibility, and 14 records with no relevant data reported were further excluded. Ultimately, 7 records were included in the present meta-analysis (Fig. 1).

Figure 1 Flow diagram of the search criteria and inclusion of the selected articles.

Characteristics of the included studies

The included studies were published between 2012 and 2021 in various countries, including the Netherlands, Lebanon, the Kingdom of Belgium, and the United Kingdom (14-20). Regarding study design, there were 5 cohort studies (14,15,17,18,20), 1 subgroup analysis of a single-arm trial (16), and 1 randomized controlled trial (19). Notably, 1,752 patients receiving kidney transplantation were involved, including 1,101 patients in the experimental group and 651 patients in the control group. The detailed information on the included studies is listed in Table I.

Table I Details of the included studies.

Table I

Details of the included studies.

First author, year	Country	Study design	Sample size of cohorts, n	Age in years, mean ± SD	Male, n (%)	Outcomes	(Ref.)
Boxma et al, 2012	Netherlands	Cohort	Experimental, 30; Control, 30	Experimental, 55.0±NK; Control, 57.0±NK	Experimental: 15 (50.0) Control: 15 (50.0)	Creatinine, CRP, systolic blood pressure	(14)
Keyzer et al, 2015	Netherlands	Cohort	Experimental, 130; Control, 129	Experimental, 48.1±12.6; Control, 54.6±10.8	Experimental: 70 (54.0) Control: 70 (54.0)	All-cause mortality, eGFR, albumin, CRP, triglycerides, hemoglobin, calcium	(15)
Mansour et al, 2017	Lebanese	Subgroup analysis of the single-arm trial	Experimental, 56; Control, 56	NK	NK	Creatinine, albumin, systolic blood pressure, diastolic blood pressure, hemoglobin, 25-hydroxyvitamin D	(16)
Evenepoel et al, 2018	The Kingdom of Belgium	Cohort	Experimental, 155; Control, 159	Experimental, 51.6±14.4; Control, 57.6±11.0	NK	Creatinine, CRP triglycerides, calcium, 25-hydroxyvitamin D	(17)
van Ballegooijen et al, 2020	Netherlands	Cohort	Experimental, 107; Control, 108	Experimental, 50.3±12.1; Control, 51.6±11.2	Experimental: 59 (55.0) Control: 68 (63.0)	All-cause mortality, eGFR, albumin, CRP, systolic blood pressure, diastolic blood pressure, triglycerides, hemoglobin	(18)
Lees et al, 2021	United Kingdom	Randomized controlled trial	Experimental, 45; Control, 45	Experimental, 5 6.3±11.1; Control, 58.9±7.8	Experimental, 32 (71.7) Control: 31 (68.9)	All-cause mortality, eGFR, creatinine, albumin, systolic blood pressure, diastolic blood pressure, triglycerides, hemoglobin, calcium, 25-hydroxyvitamin D	(19)
Kremer et al, 2021	Netherlands	Cohort	Experimental, 578; Control, 124	Experimental, 56.0±13.0; Control, 53.0±14.0	Experimental, 341 (59.0); Control, 79 (64.0)	Creatinine, systolic blood pressure, hemoglobin, 2 5-hydroxyvitamin D	(20)

[i] CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; NK, unknown.

Quality assessment

The included studies were assessed using the Newcastle-Ottawa Scale criteria, which suggested that 1 study was ranked as low risk of bias with a total score of 8(18). Additionally, 5 studies were ranked as medium risk of bias with a range of total scores from 5 to 7 (14,15,17,19,20). Notably, 1 study was ranked as a high risk of bias with a total score of 4(16); in detail, the scores of the selection bias, comparability bias, and outcome bias were evaluated as 1, 2 and 1, respectively (Table II).

Table II Assessment of the risk of bias using the Newcastle-Ottawa Scale criteria.

Table II

Assessment of the risk of bias using the Newcastle-Ottawa Scale criteria.

First author, year	Selection	Comparability	Outcome	Total score	(Ref.)
Boxma et al, 2012	2	1	2	5	(14)
Keyzer et al, 2015	3	1	2	6	(15)
Mansour et al, 2017	1	2	1	4	(16)
Evenepoel et al, 2018	2	2	1	5	(17)
van Ballegooijen et al, 2020	4	1	3	8	(18)
Lees et al, 2021	4	1	2	7	(19)
Kremer et al, 2021	3	1	3	7	(20)

All-cause mortality

A total of 3 studies reported all-cause mortality. The fixed effects model revealed that all-cause mortality was reduced in the experimental group compared to the control group [RR (95% CI): 0.72 (0.60-0.86), P<0.001]. Heterogeneity did not exist among studies (I2=45%, P=0.160; Fig. 2).

Figure 2 Comparison of all-cause mortality between the experimental group and the control group. RR, relative risk; CI, confidence interval.

Renal function indexes

A total of 3 studies reported the estimated glomerular filtration rate (eGFR). The random effects model suggested that eGFR was increased in the experimental group compared with the control group [MD (95% CI): 9.87 (1.48-18.26), P=0.021). Heterogeneity existed among these studies (I2=81%, P=0.005) (Fig. 3A). Additionally, five studies reported creatinine. After the random effects model was applied, it was found that creatinine did not differ between the two groups (MD (95% CI): -1.24 (-3.27-0.79), P=0.231). Heterogeneity existed among these studies (I2=100%, P<0.001; Fig. 3B). Moreover, five studies reported albumin. The random effects model revealed that albumin was not different between the two groups [MD (95% CI): 0.07 (-1.35-1.49), P=0.923]. Heterogeneity existed among these studies (I2=90%, P<0.001; Fig. 3C).

Figure 3 Comparison of renal function indexes between the experimental group and the control group. Pooled analysis of (A) eGFR, (B) creatine, and (C) albumin. MD, mean difference; eGFR, estimated glomerular filtration rate.

CRP

CRP was reported in four studies. Notably, the random effects model showed that CRP did not differ between the experimental group and the control group [MD (95% CI): -2.25 (-5.47-0.97), P=0.171]. Heterogeneity existed among these studies (I2=97%, P<0.001; Fig. 4).

Figure 4 Comparison of CRP between the experimental group and the control group. CRP, c-reactive protein.

Cardiovascular and bone health indexes

There were 5 studies that reported systolic blood pressure. After the random effects model was applied, it was found that systolic blood pressure did not differ between the experimental group and the control group [MD (95% CI): -1.55 (-5.34-2.25), P=0.424]. Heterogeneity existed among these studies (I2=76%, P=0.003; Fig. 5A). Additionally, 3 studies reported diastolic blood pressure. The fixed effects model showed that diastolic blood pressure remained unchanged between the two groups [MD (95% CI): -1.30 (-3.24-0.64), P=0.188]. Heterogeneity did not exist among these studies (I2=42%, P=0.181; Fig. 5B). There were 4 studies that reported triglycerides. The random effects model suggested that triglycerides did not differ between the two groups [MD (95% CI): -16.61 (-59.16-25.94), P=0.444] with heterogeneity among these studies (I2=96%, P<0.001; Fig. 5C). Moreover, 5 studies reported hemoglobin. The random effects model showed that no difference in hemoglobin was found between the two groups [MD (95% CI): 5.12 (-0.88-11.12), P=0.094] with heterogeneity among these studies (I2=90%, P<0.001; Fig. 5D).

Figure 5 Comparison of vascular and bone health indexes between the experimental group and the control group. Pooled analysis of systolic (A) blood pressure, (B) diastolic blood pressure, (C) triglycerides, (D) hemoglobin, (E) calcium, and (F) 25-hydroxyvitamin D.

A total of 3 studies reported calcium. The fixed effects model found that calcium remained unchanged between the two groups [MD (95% CI): 0.04 (-0.06-0.14), P=0.468) without heterogeneity among these studies (I2=0%, P=0.649; Fig. 5E). There were 4 studies reported on 25-hydroxyvitamin D levels. The random effects model suggested that 25-hydroxyvitamin D did not differ between the two groups [MD (95% CI): -3.16 (-7.03-0.72); P=0.110] with heterogeneity among these studies (I2=71%, P=0.015; Fig. 5F).

Publication bias and sensitivity analysis

Begg's test and Egger's test were performed to estimate the potential publication bias, which indicated that no publication bias existed for all-cause mortality, eGFR, creatinine, albumin, CRP, systolic blood pressure, diastolic blood pressure, triglycerides, hemoglobin, calcium, and 25-hydroxyvitamin D (all P>0.05; Table III).

Table III Publication bias.

Table III

Publication bias.

Outcomes	Number of included studies	P-value, Begg's test	P-value, Egger's test
All-cause mortality	3	0.602	0.310
eGFR	3	0.117	0.173
Creatinine	5	0.327	0.644
Albumin	4	0.497	0.351
CRP	4	0.497	0.192
Systolic blood pressure	5	1.000	0.560
Diastolic blood pressure	3	0.120	0.300
Triglycerides	4	0.500	0.060
Hemoglobin	5	1.000	0.592
Calcium	3	0.602	0.854
25-hydroxyvitamin D	4	1.000	0.265

[i] eGFR, estimated glomerular filtration rate; CRP, C-reactive protein.

The sensitivity analysis showed that omitting Keyzer et al (15) or van Ballegooijen et al (18) resulted in eGFR remaining unchanged between the experimental group and the control group. Meanwhile, omitting Evenepoel et al (17) resulted in a decrease in CRP in the experimental group compared to the control group. Omitting Boxma et al (14) may have contributed to systolic blood pressure reduction in the experimental group vs. the control group. Additionally, hemoglobin was increased in the experimental group compared to the control group after omitting Lees et al (19). Apart from these, the RR of all-cause mortality, as well as the MD of creatinine, albumin, diastolic blood pressure, triglycerides, calcium, and 25-hydroxyvitamin D did not significantly change by omitting any single study, which suggested the stability of this meta-analysis (Table IV).

Table IV Sensitivity analysis.

Table IV

Sensitivity analysis.

		95% Confidence interval
Omitted study	Estimate	Lower	Upper
All-cause mortality, relative risk
Keyzer et al, 2015	0.47	0.27	0.81
van Ballegooijen et al, 2020	0.80	0.66	0.95
Lees et al, 2021	0.73	0.61	0.88
Combined	0.72	0.60	0.86
eGFR, ml/min/1.73 m2, MD
Keyzer et al, 2015	6.57	-5.32	18.45
van Ballegooijen et al, 2020	8.10	-7.06	23.25
Lees et al, 2021	13.75	10.53	16.98
Combined	9.87	1.48	18.26
Creatinine, mg/dl, MD
Boxma et al, 2012	-1.53	-4.04	0.99
Mansour et al, 2017	-1.58	-4.05	0.90
Evenepoel et al, 2018	-1.30	-3.90	1.31
Lees et al, 2021	-1.58	-4.05	0.90
Kremer et al, 2021	-0.16	-0.57	0.26
Combined	-1.24	-3.27	0.79
Albumin, g/l, MD
Keyzer et al, 2015	-0.51	-1.27	0.25
Mansour et al, 2017	0.41	-1.30	2.12
van Ballegooijen et al, 2020	0.06	-1.96	2.08
Lees et al, 2021	0.37	-1.35	2.09
Combined	0.07	-1.35	1.49
CRP, mg/l, MD
Boxma et al, 2012	-2.95	-7.31	1.42
Keyzer et al, 2015	-2.72	-7.31	1.87
Evenepoel et al, 2018	-0.66	-1.09	-0.23
van Ballegooijen et al, 2020	-2.91	-7.32	1.49
Combined	-2.25	-5.47	0.97
Systolic blood pressure, mmHg, MD
Boxma et al, 2012	-3.66	-6.09	-1.23
Mansour et al, 2017	-1.33	-6.23	3.56
van Ballegooijen et al, 2020	-0.65	-4.80	3.50
Lees et al, 2021	-2.22	-6.43	1.98
Kremer et al, 2021	-0.47	-4.73	3.79
Combined	-1.55	-5.34	2.25
Diastolic blood pressure, mmHg, MD
Mansour et al, 2017	-0.87	-3.23	1.50
van Ballegooijen et al, 2020	-0.54	-3.34	2.26
Lees et al, 2021	-2.08	-4.18	0.03
Combined	-1.30	-3.24	0.64
Triglycerides, mg/dl, MD
Keyzer et al, 2015	4.63	-21.71	30.97
Evenepoel et al, 2018	-22.10	-77.78	33.58
van Ballegooijen et al, 2020	-15.38	-74.05	43.29
Lees et al, 2021	-31.25	-75.69	13.20
Combined	-16.61	-59.16	25.94
Hemoglobin, g/l, MD
Keyzer et al, 2015	4.47	-3.30	12.24
Mansour et al, 2017	6.48	-0.15	13.12
van Ballegooijen et al, 2020	5.27	-2.60	13.14
Lees et al, 2021	6.55	0.13	12.96
Kremer et al, 2021	3.06	-0.71	6.82
Combined	5.12	-0.88	11.12
Calcium, mg/dl, MD
Keyzer et al, 2015	0.07	-0.07	0.20
Evenepoel et al, 2018	0.00	-0.13	0.13
Lees et al, 2021	0.05	-0.07	0.16
Combined	0.04	-0.06	0.14
25-hydroxyvitamin D, nmol/l, MD
Mansour et al, 2017	-4.12	-8.76	0.53
Evenepoel et al, 2018	-0.90	-3.82	2.02
van Ballegooijen et al, 2020	-3.78	-8.65	1.09
Lees et al, 2021	-3.29	-7.99	1.40
Combined	-3.16	-7.03	0.72

[i] MD, mean difference; CI, confidence interval; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein.

Discussion

Vitamin K deficiency is very common in patients receiving kidney transplantation, which may ultimately contribute to an increase in all-cause mortality (15). Therefore, several studies have explored the effect of vitamin K sufficiency on all-cause mortality in patients receiving kidney transplantation (15,18,19). A previous study found that higher vitamin K status is related to reduced all-cause mortality in patients receiving kidney transplantation (15). Additionally, another study also showed that vitamin K sufficiency estimates decreased premature mortality in patients receiving kidney transplantation (18). The present meta-analysis discovered that higher vitamin K status or supplementation of vitamin K was related to decreased all-cause mortality in patients receiving kidney transplantation. The possible reasons may be: i) Vitamin K may inhibit the progression of vascular calcification by increasing the activity of matrix Gla protein (MGP) by accelerating γ-carboxylation (25,26); ii) vitamin K may also improve bone health by regulating osteocalcin (27,28). Notably, vascular calcification and bone damage were two major causes of mortality in patients receiving kidney transplantation (29), and vitamin K can improve these situations as discussed above. As a result, vitamin K may reduce all-cause mortality in these patients.

This meta-analysis also explored the effect of vitamin K on improving renal function in patients receiving kidney transplantation, and it was found that a higher vitamin K status or supplementation of vitamin K was related to increased eGFR in patients receiving kidney transplantation. A possible reason would be that vitamin K may activate MGP through carboxylation to improve renal function, which further led to the increase of eGFR (30). Thus, a positive correlation was found between vitamin K status or supplementation and eGFR in patients receiving kidney transplantation. Notably, heterogeneity existed among the analyzed 3 studies; meanwhile, sensitivity analysis displayed that omitting Keyzer et al (15) or van Ballegooijen et al (18) affected the results of eGFR, which indicated the notable weight these two articles had on the outcomes. Thus, these findings still require additional studies to verify these results. In addition, the present meta-analysis also observed that higher vitamin K status or supplementation of vitamin K was slightly associated with reduced CRP in patients receiving kidney transplantation, but this was statistically significant. A possible interpretation may be that vitamin K may reduce inflammation by regulating the nuclear factor κB pathway, a Gla-rich protein (31,32). However, heterogeneity existed among the four analyzed studies. Omitting Evenepoel et al (17) affected the results of CRP, highlighting the notable weight of this study on the results. Thus, this finding still requires further exploration.

The effect of vitamin K on improving vascular and bone health is contested based on previous studies (15,16,18-20). The present meta-analysis found that vitamin K status or supplementation of vitamin K was not related to systolic blood pressure, diastolic blood pressure, triglycerides, hemoglobin, calcium, or 25-hydroxyvitamin D in patients receiving kidney transplantation. A possible reason may be that the disease conditions were complicated in patients after kidney transplantation, and the change of a single factor (vitamin K) does not greatly influence these vascular and bone health indexes; thus, the benefits of vitamin K alone in improving vascular and bone health would not be notable (27,33,34). Heterogeneity of systolic blood pressure, triglycerides, hemoglobin, calcium, and 25-hydroxyvitamin D existed among the analyzed studies; meanwhile, sensitivity analysis found that omitting Boxma et al (14) and Lees et al (19) affected the results of systolic blood pressure and hemoglobin, respectively. this highlighted the notable weight of these two studies on the corresponding results. Therefore, these findings require further studies to confirm the results.

Although several interesting findings were discovered in the present meta-analysis, some limitations should be noted: i) Although robustness assessed by sensitivity analysis was acceptable, omitting certain articles did affect the corresponding results; thus, additional studies are required to further improve the reliability of the results; ii) most of the included studies were cohort studies; thus, the findings of this meta-analysis should be further validated; and iii) one included study was ranked as high risk of bias according to the Newcastle-Ottawa Scale criteria, which may have interfered with the results.

In conclusion, vitamin K may improve all-cause mortality and renal function in patients receiving kidney transplantation. Clinically, the intake of vitamin K after kidney transplantation may improve the clinical outcomes of these patients. However, additional large-scale studies are required to validate these findings.

Acknowledgements

Not applicable.

Funding

Funding: This study was supported by the Basic Research Program of Guizhou Province (Guizhou Science and Technology Combination Foundation) [grant no. ZK (2023) General 380].

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

ZS and YN contributed to the research design, data analysis, writing the paper, and critical review of the paper. KZ, GL, and FY collected the data and wrote the paper. SC and LJ contributed to the data analysis and critical review of the paper. ZS and YN confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References