TYPE Systematic Review

PUBLISHED 08 October 2024

DOI 10.3389/fphar.2024.1440875

Management of blood lipids in

OPEN ACCESS post-kidney transplant patients: a
EDITED BY
Marcus Tolentino Silva,
University of Brasilia, Brazil
systematic review and network
REVIEWED BY
Sara Shaheen,
meta-analysis
Ain Shams University, Egypt
Lamia M. El Wakeel,
Ain Shams University, Egypt
Bohan Luo 1,2†, Shan Zhong 2†, Xiaoxiao Wang 2, Pu Guo 2, Yifu Hou 2
*CORRESPONDENCE
and Wenjia Di 2*
Wenjia Di, 1
School of Medicine, University of Electronic Science and Technology of China, Chengdu, China, 2Organ
diwenjia@uestc.edu.cn
Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and
† Technology of China, Chengdu, Sichuan, China
These authors have contributed equally to this
work and share first authorship

RECEIVED 30 May 2024

ACCEPTED 24 September 2024
PUBLISHED 08 October 2024
Introduction: The primary objective of this systematic review was to provide an
CITATION overview of the efficacy and safety of various lipid-lowering therapies in patients
Luo B, Zhong S, Wang X, Guo P, Hou Y and Di W
post-kidney transplant (PKT), given the limited existing literature. Considering the
(2024) Management of blood lipids in post-
kidney transplant patients: a systematic review restricted number of available studies, this work aimed to summarize the existing
and network meta-analysis. evidence regarding the effectiveness of different lipid-lowering treatments in PKT
Front. Pharmacol. 15:1440875.
patients. The effects of various lipid-lowering therapeutic regimens on lipid levels
doi: 10.3389/fphar.2024.1440875
were compared, and their safety was assessed, with the heterogeneity of
COPYRIGHT
© 2024 Luo, Zhong, Wang, Guo, Hou and Di.
treatment protocols acknowledged.
This is an open-access article distributed under
the terms of the Creative Commons Attribution
Material and Methods: Randomized controlled trials investigating different
License (CC BY). The use, distribution or treatment regimens (DTRs) for regulating lipid levels in PKT patients were
reproduction in other forums is permitted, systematically retrieved from PubMed, Cochrane Library, and Embase, from
provided the original author(s) and the
copyright owner(s) are credited and that the
inception to March 2024. Literature quality was assessed employing the
original publication in this journal is cited, in Cochrane risk of bias assessment tool. Data analysis and graphical
accordance with accepted academic practice. representation were performed employing RevMan5.3 and Stata 20.0. The
No use, distribution or reproduction is
permitted which does not comply with these
surface under the cumulative ranking area (SUCRA) compared the effects of
terms. DTRs on lipid profiles, incidence of adverse events, and all-cause mortality in
PKT patients.
Results: Fifteen studies were included, comprising 5,768 PKT patients and
involving 9 treatment regimens. The results revealed that, for changes in high-
density lipoprotein cholesterol (HDL-C), the SUCRA rankings from highest to
lowest among PKT patients receiving DTRs were statins + ezetimibe (70%),
placebo (61.5%), fibrates (57.2%), statins (44.1%), and fish oil (17.3%). Regarding
changes in low-DL-C (LDL-C), the SUCRA rankings from highest to lowest among
PKT patients receiving DTRs were statins (68.2%), statins + ezetimibe (67.5%), fish
oil (53.4%), fibrates (34.5%), and placebo (26.5%). For the change in total
cholesterol (TC) levels, a network meta-analysis (NMA) revealed that among
PKT patients receiving DTRs, the SUCRA rankings from highest to lowest for TC
change were statins + ezetimibe (97.6%), proprotein convertase subtilisin/kexin
type 9 inhibitors (PCSK9 inhibitors) (74.3%), fish oil (64.3%), statins (61.6%), fibrates
(47.2%), placebo (31.6%), calcineurin phosphatase inhibitors (11.9%), and
immunosuppressants (11.4%). Regarding the change in triglyceride (TG) levels,
a NMA showed that among PKT patients receiving DTRs, the SUCRA rankings
from highest to lowest for TG change were fibrates (99.9%), statins (68.9%),
PCSK9 inhibitors (66.6%), statins + ezetimibe (55.1%), placebo (49.2%), fish oil
(45.0%), immunosuppressants (7.8%), and calcineurin phosphatase inhibitors

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(7.6%). For the occurrence of kidney transplant failure, a NMA revealed that among
PKT patients receiving DTRs, the SUCRA rankings from highest to lowest for
reducing the incidence of kidney transplant failure were PCSK9 inhibitors
(69.0%), calcineurin phosphatase inhibitors (63.0%), statins (61.5%), placebo
(55.1%), steroids (51.8%), immunosuppressants (27.1%), and fibrates (22.5%).
Regarding all-cause mortality, a NMA showed that among PKT patients
receiving DTRs, the SUCRA rankings from highest to lowest for reducing all-
cause mortality were PCSK9 inhibitors (90.5%), statins (55.8%), and placebo (3.7%).

Conclusion: In reducing lipid levels in PKT patients, combination therapy with

statins and ezetimibe demonstrated notable advantages and higher effectiveness.
PCSK9 inhibitors exhibited greater advantages in reducing adverse events and
mortality rates in PKT patients, with higher safety.

KEYWORDS

post-kidney transplantation, lipid-lowering drug therapy, lipid profiles, adverse events,

mortality rate, meta-analysis

1 Introduction mechanisms and are commonly used in conjunction with other

lipid-lowering agents (Stallone et al., 2005). Niacin-based drugs not
Dyslipidemia is one of the more common complications only reduce LDL-C and triglycerides (TG) but also increase high-
observed in patients following kidney transplantation. It not only density lipoprotein cholesterol (HDL-C). Zhu et al. (2023) reported a
directly impacts the long-term survival rate of the transplanted high incidence of adverse effects associated with niacin-based
kidney but also increases the risk of cardiovascular diseases and medications, which may limit their clinical application. However,
post-transplant complications. Post-transplant dyslipidemia their efficacy in specific patient populations remains significant.
typically includes characteristics such as elevated cholesterol, Fibrates are primarily used to treat hypertriglyceridemia and low
increased triglycerides, elevated low-density lipoprotein (LDL), HDL-C levels, effectively reducing cholesterol levels and increasing
and reduced high-density lipoprotein (HDL). These dyslipidemic HDL-C (Chen et al., 2008). Commonly used fibrates include
alterations are often closely associated with immunosuppressive fenofibrate and bezafibrate. These medications function by
therapy and the inflammatory state related to chronic kidney activating peroxisome proliferator-activated receptor alpha
disease. Immunosuppressants can directly or indirectly affect (PPARα), which regulates lipoprotein metabolism and has
lipid metabolism, leading to alterations in blood lipid levels important implications for improving cardiovascular outcomes
(Williams et al., 2001; Weir et al., 2015). (Baños et al., 2008). In post-kidney transplant (PKT) patients, drug
Common lipid-lowering medications include statins, ezetimibe, management is particularly complex and requires careful selection of
proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, appropriate lipid-lowering agents based on individual patient
niacin, and fibrates. Statins, the most used class of lipid-lowering characteristics and specific conditions to ensure drug safety. For
drugs, reduce cholesterol synthesis by inhibiting 3-hydroxy-3- instance, in patients with post-transplant hypercholesterolemia,
methylglutaryl coenzyme A reductase. Research by Goldberg et al. statin therapy necessitates close monitoring of liver function and
(1996) demonstrated that statins significantly lower low-density muscle enzyme levels to prevent adverse drug reactions. Ezetimibe
lipoprotein cholesterol (LDL-C) levels and possess anti- and PCSK9 inhibitors also show promising potential in this patient
inflammatory properties, which can delay the progression of population, but adjustments based on individual tolerability are
atherosclerosis. This combined effect ultimately reduces the risk of necessary (Coco et al., 2012). Currently, research on lipid
severe cardiovascular events such as myocardial infarction and stroke. management strategies and pharmacotherapy in PKT patients is
Ezetimibe, a representative drug in the ezetimibe class, primarily relatively limited. Existing studies primarily focus on the
lowers blood lipid levels by inhibiting intestinal cholesterol absorption application and efficacy of various lipid-lowering medications in
(Vanrenterghem et al., 2011). Research by Pascual et al. (2005a) clinical practice. However, evidence on the specific efficacy, safety,
indicated that the combination of ezetimibe and statins results in a and long-term prognosis of these treatments in post-transplant
more significant reduction in blood lipids and improves therapeutic patients remains insufficient. Therefore, it is crucial to conduct
outcomes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) systematic research to explore lipid management strategies in PKT
inhibitors, a rapidly advancing class of biotechnology products, patients, aiming to optimize treatment regimens while reducing
function by inhibiting PCSK9 activity, which significantly increases cardiovascular risk and post-transplant complications.
the expression levels of low-density lipoprotein receptors (LDLR) on This work was to demonstrate the efficacy and safety of different
hepatocyte surfaces, thereby markedly reducing LDL-C. Despite their lipid-lowering medications in PKT patients, comparing their effects
high cost, these drugs have demonstrated exceptional lipid-lowering on dyslipidemia and the long-term impact on renal transplant
efficacy in patients at extremely high or very high risk, and are often function and cardiovascular health. Through this research, we
used in combination with statins (Rodriguez et al., 1997; Tedesco- aimed to provide more effective drug treatment strategies and
Silva et al., 2019). Niacin and its derivatives, collectively referred to as clinical guidance for lipid management in PKT patients, further
niacin-based drugs, modulate lipid metabolism through multiple improving patient prognosis and quality of life.

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FIGURE 1
Flowchart of literature selection.

2 Methodologies (((((((((((Kidney Transplantation[Title/Abstract]) OR (Renal

Transplantation[Title/Abstract])) OR (Renal Transplantations
2.1 Criteria for literature inclusion [Title/Abstract])) OR (Transplantations, Renal[Title/Abstract]))
and exclusion OR (Transplantation, Renal[Title/Abstract])) OR (Grafting,
Kidney[Title/Abstract])) OR (Kidney Grafting[Title/Abstract]))
Inclusion criteria: i) Study type: double-blind or single-blind OR (Transplantation, Kidney[Title/Abstract])) OR (Kidney
randomized controlled trials (RCTs); ii) Study population: PKT Transplantations[Title/Abstract])) OR (Transplantations, Kidney
patients; iii) Intervention: experimental groups receiving different [Title/Abstract])) OR (Lipid Regulating Agents[Title/Abstract])))
treatment regimens (DTRs) with intervention and follow-up AND (“Lipid Regulating Agents”[Mesh])) OR ((((((Lipid Regulating
durations of more than 1 month, while control groups receive Agents[Title/Abstract]) OR (Agents, Lipid Regulating[Title/
placebos or various treatment medications compared to the Abstract])) OR (Regulating Agents, Lipid[Title/Abstract])) OR
experimental group; iv) Outcome measures: changes in lipid-related (Lipid Regulating Drugs[Title/Abstract])) OR (Drugs, Lipid
indicators before and after treatment, adverse reactions, mortality, etc. Regulating[Title/Abstract])) OR (Regulating Drugs, Lipid[Title/
Exclusion criteria: i) Study participants with other renal diseases Abstract]))) AND “Randomized Controlled Trial”. For Cochrane
or severe comorbidities that may affect outcome indicators; ii) Library and Embase, slight adjustments were made to the
Literature such as reviews, case reports, and conference abstracts; search keywords.
iii) Literature with unclear or unextractable outcome indicators or
outcome data; iv) Literature with unclear intervention measures; v)
Literature not in Chinese or English languages. 2.3 Data extraction

Two authors independently conducted literature search,

2.2 Literature retrieval strategy screening, and full-text review regarding the above criteria.
Relevant data were independently extracted by authors into a
Using computerized searches, relevant literature published from pre-designed Excel spreadsheet. Extracted data included
the inception of the databases up to March 2024 was retrieved from publication year, first author name, sample size, study design,
databases PubMed, Cochrane Library, Embase, etc. MeSH (Medical intervention measures, and outcome indicators. Outcome
Subject Headings) terms were employed in combination with indicators comprised lipid indicators (high-density lipoprotein
“AND” and “OR” logical operators for the search. The PubMed cholesterol (HDL-C), low-DL-C (LDL-C), total cholesterol (TC),
search strategy was as follows: “Kidney Transplantation”(Mesh) OR and TG), incidence rates of adverse events (including cardiovascular

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TABLE 1 Basic information.

Author Year Sample Intervention measures Number of included cases Outcome

size indicators
Intervention Control group Intervention Control
group group group
Alotaibi 2024 197 PCSK9 inhibitors Statins 98 99 CDEFH

Castro 1997 43 Statins F 25 18 ABCD

Eris 2005 2,102 Statins P 1,050 1,052 ABCDF

Flechner 2002 61 CNI Immunosuppressants (IS) 31 30 EFGH

Hausberg 2001 36 Statins P 18 18 ABCD

Holdaas 2001 364 Statins P 182 182 ABCDEH

Holdaas 2011 267 CNI P 144 123 CDFH

Jardine 2004 2,102 Statins P 1,050 1,052 ABCD

Kasiske 2001 88 BC P 36 52 ABCDF

Lebranchu 2009 192 CNI IS 95 97 BCDF

Montagnino 2008 133 Steroids P 65 68 F

Sero´n 2008 74 Statins P 39 35 ABCDFG

Sharif 2009 20 Statins P 10 10 ABCD

Van Hooff 2003 53 IS + CNI IS + Statins 25 28 G

Kohnle 2006 36 Statins Statins + Cholesterol absorption 18 18 ABCD

inhibitors (CAI)

Note: A, HDL-C; B, LDL-C; C, TC; D, TG; E, cardiovascular adverse events; F, renal transplant dysfunction; G, acute rejection reaction; H, All-Cause Mortality Rate. (PCSK9 stands for
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors; Statins refer to Statin Medications; IS, denotes Immunosuppressants; CNI, stands for Calcineurin Inhibitors; BC, refers to Bile Acid
Sequestrants; F represents Fibrates; Statins + CAI, means Statins Combined with Ezetimibe; Steroids refer to Corticosteroids; and P stands for Placebo.).

events, kidney transplant failure, acute rejection reactions), and all-

cause mortality. Continuous variables were denoted as mean ±
standard deviation, while categorical variables as frequencies. In
case of discrepancies, consensus was reached through discussion or
consultation with a third independent author.

2.4 Literature quality evaluation

The two authors utilized the Cochrane risk of bias assessment

tool (Martimbianco et al., 2023) to evaluate the quality and risk of
bias in the included study literature. The assessment criteria
included random sequence generation (selection bias), allocation
concealment (selection bias), blinding of participants and personnel
(performance bias), blinding of outcome assessment (detection
bias), incomplete outcome data (attrition bias), selective reporting
(reporting bias), and other biases. Each bias assessment was
categorized as “Low risk,” “Unclear risk,” or “High risk.”
FIGURE 2
Network evidence relationship diagram illustrating the effect of
DTRs on the change in HDL-C levels in PKT patients. (Statins denote
Statin Medications; BC stands for Bile Acid Sequestrants; F refers to
2.5 Statistical analysis
Fibrates; Statins + CAI means Statins Combined with Ezetimibe;
and P represents Placebo). The included studies were assessed for literature quality
employing RevMan5.3, and network meta-analysis (NMA) was

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FIGURE 3
NMA results of the effect of DTRs on change in HDL-C levels in PKT patients. (Statins denote Statin Medications; BC stands for Bile Acid Sequestrants;
F refers to Fibrates; Statins + CAI means Statins Combined with Ezetimibe; and P represents Placebo).

FIGURE 4
SUCRA plot depicting change in HDL-C levels among PKT patients treated with different therapeutic regimens [(A) Statins, (B) BC, (C) Fibrates (F), (D)
Statins + CAI, (E) Placebo (P)].

conducted employing Stata 20.0. Binary variables were expressed analysis to examine differences between direct and indirect
as odds ratios (OR), while continuous variables as mean comparison results. If no inconsistency was observed, a
differences (MD), with effect sizes evaluated along with their consistency model was employed for fitting analysis. In case of
95% confidence intervals (CI). Network evidence plots were inconsistency, an inconsistency model was utilized for fitting
generated, with the size of the nodes representing the sample analysis, followed by sensitivity analysis to assess result stability.
size of each intervention, and the thickness of the lines indicating The surface under the cumulative ranking area (SUCRA) curve was
the amount of direct evidence between interventions. In the utilized to rank the outcome indicators of each intervention, and a
presence of closed loops in the network plot, a loop consistency “comparison-corrected” funnel plot was generated to evaluate
test or node-splitting methodology was adopted for inconsistency small sample effects and publication bias in included studies.

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2002; Hausberg et al., 2001; Holdaas et al., 2001; Holdaas et al., 2011;
Jardine et al., 2004; Kasiske et al., 2001; Lebranchu et al., 2009;
Montagnino et al., 2008; Serón et al., 2008; Sharif et al., 2009; van
Hooff et al., 2003; Kohnle et al., 2006) were included. The literature
search process is illustrated in Figure 1.

3.2 Basic information

Fifteen relevant articles were included, comprising a total of

5,768 patients across 9 treatment modalities. All studies involved
renal transplant recipients as the study population. Table 1 presents
the basic information of the included studies.

3.3 Quality assessment

The bias analysis results of the included literature are presented

FIGURE 5
in Supplementary Figures S1, S2, indicating low risk of bias across
Network evidence diagram illustrating the impact of DTRs on the the included studies.
change in LDL-C levels in PKT patients. (Statins denote Statin
Medications; BC stands for Bile Acid Sequestrants; F refers to Fibrates;
Statins + CAI means Statins Combined with Ezetimibe; and P
represents Placebo). 3.4 Meta-analysis results

3.4.1 NMA results of the impact of DTRs on change

3 Results in HDL-C levels in PKT patients
In the included literature, 9 studies analyzed the effects of DTRs
3.1 Literature retrieval process on HDL-C levels in PKT patients, involving a total of 4,865 patients
and comprising 5 intervention measures, including statins, fibrates,
A total of 272 relevant articles were retrieved from PubMed, fish oil, statins + ezetimibe, and placebo. NMA of HDL-C level
Cochrane Library, and Embase. After removing duplicates, changes revealed that the SUCRA ranking from highest to lowest
243 articles remained. Upon title and abstract screening, among PKT patients receiving DTRs was as follows: statins +
166 articles were excluded due to reasons such as case reports, ezetimibe (70%), placebo (61.5%), fibrates (57.2%), statins
reviews, interventions not meeting criteria, diseases not meeting (44.1%), and fish oil (17.3%) (Supplementary Figure S3;
study requirements, and other non-compliance issues. Figures 2–4).
Subsequently, 77 articles underwent further screening. Full-text
articles were obtained and after thorough reading, 62 articles 3.4.2 II.NMA results of the influence of DTRs on
were excluded due to unclear outcome indicators, undefined LDL-C change magnitude in PKT patients
treatment regimens, or unavailability of data. Finally, 15 articles The included literature consisted of 9 studies analyzing the
(Alotaibi et al., 2024; Castro et al., 1997; Eris, 2005; Flechner et al., influence of DTRs on LDL-C levels in PKT patients, comprising

FIGURE 6
NMA results of the impact of DTRs on the change in LDL-C levels in PKT patients. (Statins denote Statin Medications; BC stands for Bile Acid
Sequestrants; F refers to Fibrates; Statins + CAI means Statins Combined with Ezetimibe; and P represents Placebo).

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FIGURE 7
SUCRA plot of the change in LDL-C levels in PKT patients treated with DTRs [(A): Statins, (B) BC, (C) F, (D) Statins + CAI, (E) P; Statins denote Statin
Medications; BC stands for Bile Acid Sequestrants; F refers to Fibrates; Statins + CAI means Statins Combined with Ezetimibe; and P represents Placebo].

a total of 4,865 patients across 5 intervention measures, including

statins, fibrates, fish oil, statins combined with ezetimibe, and
placebo (Supplementary Figure S4; Figures 5–7). NMA of LDL-C
change magnitude revealed that the SUCRA values, ranked from
highest to lowest, were as follows: statins (68.2%), statins combined
with ezetimibe (67.5%), fish oil (53.4%), fibrates (34.5%), and
placebo (26.5%).

3.4.3 NMA results of the impact of DTRs on the

magnitude of TC change in PKT patients
Twelve studies investigated the effects of DTRs on TC in PKT
patients, with a total of 5,521 patients and 8 intervention measures,
including PCSK9 inhibitors, statins, immunosuppressants, calcium
channel blockers, bile acid sequestrants, fish oil, statins plus
ezetimibe, and placebo. A NMA of TC change magnitude
revealed that the SUCRA values, indicating the ranking of
treatment efficacy, were highest for statins plus ezetimibe
(97.6%), followed by PCSK9 inhibitors (74.3%), fish oil (64.3%),
statins (61.6%), bile acid sequestrants (47.2%), placebo (31.6%),
calcium channel blockers (11.9%), and immunosuppressants
FIGURE 8 (11.4%) (Supplementary Figure S5; Figures 8–10).
Network evidence relationship diagram of the effect of DTRs on
the change in TC levels in PKT patients. (PCSK9 stands for Proprotein
Convertase Subtilisin/Kexin Type 9 Inhibitors; Statins refer to Statin 3.4.4 Meta-analysis results of the impacts of DTRs
Medications; IS denotes Immunosuppressants; CNI stands for on PKT patients’ TG change magnitude
Calcineurin Inhibitors; BC refers to Bile Acid Sequestrants; F
represents Fibrates; Statins + CAI means Statins Combined with Twelve studies investigated the effects of DTRs on PKT patients’
Ezetimibe; Steroids refer to Corticosteroids; and P stands for Placebo.) TG levels, comprising a total of 5,521 patients and involving
8 intervention measures, including PCSK9 inhibitors, statins,

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FIGURE 9
NMA results of the effect of DTRs on the change in TC levels in PKT patients. (PCSK9 stands for Proprotein Convertase Subtilisin/Kexin Type
9 Inhibitors; Statins refer to Statin Medications; IS denotes Immunosuppressants; CNI stands for Calcineurin Inhibitors; BC refers to Bile Acid
Sequestrants; F represents Fibrates; Statins + CAI means Statins Combined with Ezetimibe; and P stands for Placebo.)

immunosuppressants, calcium channel blockers, fibrates, fish oil, placebo (55.1%), corticosteroids (51.8%), immunosuppressants
statins plus ezetimibe, and placebo (Supplementary Figure S6; (27.1%), and fibrates (22.5%).
Figures 11–13). NMA of TG change magnitude revealed that the
SUCRA rankings, from highest to lowest, for PKT patients receiving 3.4.7 NMA results regarding the impact of DTRs on
DTRs were as follows: fibrates (99.9%), statins (68.9%), acute rejection reactions in PKT patients
PCSK9 inhibitors (66.6%), statins plus ezetimibe (55.1%), placebo Two studies examined the impact of DTRs on acute rejection
(49.2%), fish oil (45.0%), immunosuppressants (7.8%), and calcium reactions in PKT patients. These studies comprised a total of
channel blockers (7.6%). 2,176 patients and investigated two intervention measures,
including statins and a placebo (Figure 18).
3.4.5 Meta-analysis results of the influence of DTRs
on cardiovascular adverse events in PKT patients 3.4.8 NMA results on the impact of DTRs on all-
Two studies assessed the impact of DTRs on cardiovascular cause mortality in PKT patients
adverse events in PKT patients, comprising a total of 561 patients Four studies analyzed the impact of DTRs on all-cause mortality
and involving three intervention strategies: PCSK9 inhibitors, in PKT patients, comprising a total of 2,699 patients and involving
statins, and placebo (Figure 14). three intervention measures, including PCSK9 inhibitors, statins,
and placebo (Supplementary Figure S8; Figures 19–21). A NMA on
3.4.6 NMA results of the impact of treatment all-cause mortality revealed that the SUCRA values, indicating the
regimens on PKT patients’ graft failure effectiveness in reducing all-cause mortality, ranked from highest to
Incorporating 8 studies, the analysis examined the impact of lowest as follows: PCSK9 inhibitors (90.5%), statins (55.8%), and
treatment regimens on PKT patients’ graft failure, encompassing a placebo (3.7%).
total of 3,114 patients and 7 intervention approaches, including
PCSK9 inhibitors, statins, immunosuppressants, calcium channel
blockers, fibrates, corticosteroids, and placebos (Supplementary 3.5 Bias analysis
Figure S7; Figures 15–17). Conducting a NMA on graft failure, it
was observed that the SUCRA values, indicating the likelihood of By plotting a standard funnel plot for the analysis of publication
reducing graft failure occurrence, ranked in descending order as bias in the included literature, it was observed that the funnel plot
follows for the various treatment approaches: PCSK9 inhibitors exhibited good symmetry, and the included studies were evenly
(69.0%), calcium channel blockers (63.0%), statins (61.5%), distributed, indicating a minimal publication bias in the study

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FIGURE 10
SUCRA diagram depicting the magnitude of TC changes in PKT patients treated with different therapeutic regimens [(A) for PCSK9 inhibitors, (B) for
Statins, (C) for IS, (D) for CNI, (E) for BC, (F) for F, (G) for Statins + CAI, (H) for P; PCSK9 stands for Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors;
Statins refer to Statin Medications; IS denotes Immunosuppressants; CNI stands for Calcineurin Inhibitors; BC refers to Bile Acid Sequestrants; F
represents Fibrates; Statins + CAI means Statins Combined with Ezetimibe; and P stands for Placebo].

designs of the included literature. The standard funnel plot is Corticosteroids may also contribute to dyslipidemia, particularly
presented in Figure 22. with long-term use (Lepre et al., 1999; Pipeleers et al., 2021).
Pharmacological treatment remains a crucial strategy for
managing dyslipidemia, and selecting medications with high
3.6 GRADE evidence quality assessment efficacy and safety profiles is essential for promoting patient health.
To further evaluate the efficacy of lipid-lowering therapies in
This study included a total of eight outcome measures, with managing elevated lipid levels in PKT patients, this study conducted
HDL-C, LDL-C, TC, TG, and renal transplant failure as a systematic review and network meta-analysis of lipid management
intermediate quality evidence, and cardiovascular and medications for these patients. The selection of medications for
cerebrovascular adverse reactions, acute rejection, and all-cause network meta-analysis was based on their ability to adjust lipid levels
mortality as low-quality evidence (Table 2). in PKT patients, as well as their safety and tolerability. For instance,
statins are widely used due to their potent LDL-C lowering effects;
ezetimibe, a cholesterol absorption inhibitor, can enhance the
4 Discussion efficacy of statins; fibrates are primarily used to reduce
triglyceride levels; and PCSK9 inhibitors have garnered attention
PKT patients often face the necessity of using for their significant LDL-C lowering effects and favorable safety
immunosuppressants, which can affect metabolism and lead to profile. Our study results indicated that, in the NMA of HDL-C
dyslipidemia (Fuentes-Orozco et al., 2018; Jafari et al., 2017). change magnitude, the SUCRA values for PKT patients treated with
Long-term administration of these immunosuppressants is different therapeutic regimens ranked from highest to lowest as
typically required to prevent organ rejection. Different classes of follows: statins + ezetimibe (70%), placebo (61.5%), fibrates (57.2%),
immunosuppressants may have varying impacts on lipid statins (44.1%), and fish oil (17.3%). In the NMA of LDL-C change
metabolism, resulting in dyslipidemia. For instance, CNIs such as magnitude, the SUCRA values for PKT patients treated with
cyclosporine and tacrolimus have been shown to influence lipid different therapeutic regimens ranked from highest to lowest as
metabolism. Cyclosporine can elevate levels of LDL-C and TC, while follows: statins (68.2%), statins + ezetimibe (67.5%), fish oil (53.4%),
tacrolimus may increase TG levels. Additionally, mycophenolate fibrates (34.5%), and placebo (26.5%). In the NMA of TC change
mofetil (MMF) generally does not significantly affect lipid levels, but magnitude, the SUCRA values for PKT patients treated with
its combination with CNIs may exacerbate lipid abnormalities. different therapeutic regimens ranked from highest to lowest as

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follows: statins + ezetimibe (97.6%), PCSK9 inhibitors (74.3%), fish

oil (64.3%), statins (61.6%), fibrates (47.2%), placebo (31.6%),
calcium channel blockers (11.9%), and immunosuppressants
(11.4%). In the NMA of TG change magnitude, the SUCRA
values for PKT patients treated with different therapeutic
regimens ranked from highest to lowest as follows: fibrates
(99.9%), statins (68.9%), PCSK9 inhibitors (66.6%), statins +
ezetimibe (55.1%), placebo (49.2%), fish oil (45.0%),
immunosuppressants (7.8%), and calcium channel blockers
(7.6%). In PKT patients, common lipid abnormalities include
hypercholesterolemia, hypertriglyceridemia, and low levels of
HDL-C. These abnormalities are closely associated with an
increased risk of CVD, which is a leading cause of non-infectious
mortality in PKT patients. Low HDL-C levels are generally linked to
the progression of atherosclerosis, whereas elevated HDL-C levels
are considered to have an atheroprotective effect. Similarly,
increased levels of LDL-C and TG can accelerate atherosclerosis,
thereby increasing the risk of coronary artery disease and other
cardiovascular events. In terms of reducing lipid levels in PKT
patients, the combination of statins and ezetimibe offers a
FIGURE 11
Network evidence relationship diagram of the effect of DTRs on significant advantage. Statins primarily function by inhibiting
the magnitude of TG changes in PKT patients. (PCSK9 stands for cholesterol synthesis, which can significantly increase HDL-C
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors; Statins refer levels. Ezetimibe, a cholesterol absorption inhibitor, can also
to Statin Medications; IS denotes Immunosuppressants; CNI
stands for Calcineurin Inhibitors; BC refers to Bile Acid Sequestrants; F elevate HDL-C levels. The combination of statins and ezetimibe
represents Fibrates; Statins + CAI means Statins Combined with can have a synergistic effect, substantially increasing HDL-C levels
Ezetimibe; and P stands for Placebo). and thus promoting cholesterol reverse transport and metabolism,
which reduces the risk of atherosclerosis (Kosch et al., 2004).

FIGURE 12
NMA results of the effect of DTRs on the magnitude of TG changes in PKT patients. (PCSK9 stands for Proprotein Convertase Subtilisin/Kexin Type
9 Inhibitors; Statins refer to Statin Medications; IS denotes Immunosuppressants; CNI stands for Calcineurin Inhibitors; BC refers to Bile Acid
Sequestrants; F represents Fibrates; Statins + CAI means Statins Combined with Ezetimibe; and P stands for Placebo).

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FIGURE 13
SUCRA plot of the changes in TG levels in PKT patients treated with DTRs [(A) for PCSK9 inhibitors, (B) for Statins, (C) for IS, (D) for CNI, (E) for BC, (F)
for F, (G) for Statins + CAI, (H) for P; PCSK9 stands for Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors; Statins refer to Statin Medications; IS
denotes Immunosuppressants; CNI stands for Calcineurin Inhibitors; BC refers to Bile Acid Sequestrants; (F) represents Fibrates; Statins + CAI means
Statins Combined with Ezetimibe; and P stands for Placebo].

abnormalities are often exacerbated by chronic renal

insufficiency, and ezetimibe can effectively address these issues.
PKT patients frequently exhibit multiple types of dyslipidemia,
including elevated LDL-C, high TG, and low HDL-C. The
combination of statins and ezetimibe can address multiple lipid
abnormalities simultaneously, resulting in more comprehensive
lipid regulation (Krämer et al., 2016). Long-term, effective lipid
management is crucial for reducing the incidence of cardiovascular
events, improving patient quality of life, and prolonging the survival
of transplanted organs. By lowering LDL-C levels, the progression of
atherosclerosis can be mitigated, thereby reducing the risk of
myocardial infarction and stroke. Additionally, the use of
medications with fewer side effects can diminish patient
resistance to treatment and improve adherence. Cost-effectiveness
analyses indicate that although some newer lipid-lowering
medications may be expensive, their significant reduction in
cardiovascular event risk may make them a cost-effective option
in the long run.
FIGURE 14
PKT patients with dyslipidemia are at increased risk of
Network evidence map of the effects of DTRs on cardiovascular cardiovascular and cerebrovascular adverse events. Prolonged
and cerebrovascular adverse events in PKT patients. (PCSK9 stands for
dyslipidemia, especially high cholesterol and high TGs, increases
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors; Statins refer
to Statin Medications; and P stands for Placebo). the risk of atherosclerosis, leading to vascular narrowing, plaque
formation, and even thrombosis, thereby elevating the risk of
cardiovascular events such as angina, myocardial infarction, and
Research indicated that ezetimibe can significantly lower TG levels stroke. Moreover, dyslipidemia adversely affects vascular endothelial
by inhibiting their absorption in the intestine [(Lebranchu et al., cells and smooth muscle cells, resulting in vascular dysfunction,
2009); (Lal et al., 1995)]. In PKT patients, lipid metabolism thrombosis, and vascular injury (Flechner et al., 2002). Particularly

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Luo et al. 10.3389/fphar.2024.1440875

other lipid abnormalities may affect the function of the immune

system, particularly under immunosuppressive therapy, potentially
exacerbating immune dysfunction and increasing the risk of acute
rejection (Fassett et al., 2010). Lipid abnormalities also impact
vascular health, increasing the risk of endothelial damage, plaque
formation, and other adverse effects, which may negatively affect the
perfusion and function of the transplanted kidney, thereby
increasing the risk of acute rejection. Studies have shown that
PKT patients with lipid abnormalities may have an increased risk
of acute rejection and mortality compared to those with normal lipid
levels (Jardine et al., 2005). Therefore, analyzing the role of lipid-
lowering drugs in reducing the incidence of cardiovascular adverse
events is of paramount importance.
To further investigate the impact of lipid-lowering drugs on
cardiovascular adverse events and all-cause mortality, this study
conducted a meta-analysis. The results showed that in the analysis of
PKT failure, the SUCRA for reducing the incidence of transplant
failure in PKT patients receiving DTRs was highest for
PCSK9 inhibitors (69.0%), followed by calcium channel blockers
(63.0%), statins (61.5%), placebo (55.1%), steroids (51.8%),
immunosuppressants (27.1%), and fibrates (22.5%). In the
FIGURE 15 analysis of all-cause mortality, the SUCRA for reducing all-cause
Network evidence map of the effects of DTRs on graft failure in
PKT patients. (PCSK9 stands for Proprotein Convertase Subtilisin/ mortality in PKT patients receiving DTRs was highest for
Kexin Type 9 Inhibitors; Statins refer to Statin Medications; IS denotes PCSK9 inhibitors (90.5%), followed by statins (55.8%) and
Immunosuppressants; CNI stands for Calcineurin Inhibitors; BC placebo (3.7%). It was observed that PCSK9 inhibitors
refers to Bile Acid Sequestrants; Steroids represents Steroids; and P
stands for Placebo). demonstrate significant advantages in reducing adverse events
and mortality rates in PKT patients. PCSK9 primarily functions
to facilitate the degradation of low-density lipoprotein receptors
(LDL receptors), leading to an increase in LDL-C in the bloodstream
after kidney transplantation, the use of immunosuppressive drugs (Pascual et al., 2005b). PCSK9 inhibitors work by blocking the
may exacerbate dyslipidemia, further increasing the risk of binding of PCSK9 to LDL receptors, thereby increasing the quantity
cardiovascular adverse events. Additionally, high cholesterol and of LDL receptors in the liver, promoting the clearance of LDL-C, and

FIGURE 16
NMA results of the effects of DTRs on graft failure in PKT patients. (PCSK9 stands for Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors; Statins
refer to Statin Medications; IS denotes Immunosuppressants; CNI stands for Calcineurin Inhibitors; BC refers to Bile Acid Sequestrants; Steroids
represents Steroids; and P stands for Placebo).

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Luo et al. 10.3389/fphar.2024.1440875

FIGURE 17
SUCRA plot of the impact of DTRs on PKT patients’ graft failure. [(A) for PCSK9 inhibitors, (B) for Statins, (C) for IS, (D) for CNI, (E) for BC, (F) for
Steroids, (G) for P; PCSK9 stands for Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors; Statins refer to Statin Medications; IS denotes
Immunosuppressants; CNI stands for Calcineurin Inhibitors; BC refers to Bile Acid Sequestrants; Steroids represents Steroids; and P stands for Placebo].

FIGURE 18
FIGURE 19
Network evidence diagram of the impact of DTRs on acute Network evidence diagram of the impact of DTRs on all-cause
rejection reactions in PKT patients. (Statins and P stand for Statin mortality in PKT patients. (PCSK9 stands for Proprotein Convertase
Medications and Placebo, respectively). Subtilisin/Kexin Type 9 Inhibitors; Statins denote Statin Medications;
and P refers to Placebo).

consequently reducing LDL-C levels in the bloodstream (Artz et al., cardiovascular events. PKT patients often face increased
2003; Santos et al., 2001). In PKT patients, PCSK9 inhibitors can cardiovascular risks, so lowering LDL-C levels can effectively
significantly lower LDL-C, thereby reducing the risk of prevent asthma attacks (Norby et al., 2009). PCSK9 inhibitors

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Luo et al. 10.3389/fphar.2024.1440875

FIGURE 20
NMA results of the impact of DTRs on all-cause mortality in PKT patients. (PCSK9 stands for Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors;
Statins denote Statin Medications; and P refers to Placebo).

FIGURE 21
SUCRA plot of all-cause mortality in PKT patients treated with various treatment strategies [(A) for PCSK9 inhibitors, (B) for statins, (C) for P;
PCSK9 stands for Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors; Statins denote Statin Medications; and P refers to Placebo].

may reduce the formation of atherosclerotic plaques, potentially have employed different doses of the same drug. These discrepancies
contributing to a reduction in immune system activation and could lead to inconsistencies in results, thereby affecting our
inflammatory responses, thereby lowering the risk of acute understanding of the relative efficacy of various treatment
rejection (Melchor and Gracida, 1998). PCSK9 inhibitors help regimens. Additionally, inconsistencies in drug dosages and
improve endothelial function, reduce vascular damage and treatment durations across studies may also impact the
thrombus formation, thereby protecting the vascular health of the consistency of efficacy assessments. Lastly, this study did not
transplanted kidney, reducing damage to transplant kidney sufficiently account for the effects of factors such as race and
function, and possessing positive clinical implications (Kliem gender on drug efficacy, which represents a limitation. Future
et al., 1996). research should further investigate the underlying mechanisms of
This study primarily relied on existing literature, which may be lipid abnormalities, particularly those associated with
subject to publication bias, with positive results being more likely to immunosuppressants. For example, immunosuppressants such as
be published. Furthermore, the included studies may vary in design, cyclosporine and tacrolimus have been shown to affect lipid
sample size, and patient characteristics, potentially introducing metabolism. Moreover, additional randomized controlled trials are
heterogeneity. Notably, differences between control and needed to assess the long-term effects of different drug combinations,
intervention groups across studies may affect the evaluation of the while considering a broader range of demographic variables,
efficacy of different lipid-lowering drugs. For instance, some studies including age, sex, race, and comorbidities, to better understand
may have used varying control drugs or placebos, while others might how these factors influence treatment outcomes. Additionally,

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Luo et al. 10.3389/fphar.2024.1440875

FIGURE 22
Comparison of publication bias in the effects of various treatment strategies on lipid reduction and safety in PKT patients-corrected funnel plot. [(A)
for HDL-C, (B) for LDL-C, (C) for TC, (D) for TG, (E) for cardiovascular adverse events, (F) for transplant failure, (G) for acute rejection, (H) for all-
cause mortality].

TABLE 2 Results of GRADE evidence quality assessment included in the study.

Final result Number of Sample Risk Inconsistency Indirectness Imprecision Publication Evidence
documents size of bias quality
bias
HDL-C 9 4,865 1a 0 0 0 0 Medium level

b
LDL-C 9 4,865 0 0 0 1 0 Medium level
a
TC 12 5,521 1 0 0 0 0 Medium level

TG 12 5,521 1a 0 0 0 0 Medium level

Adverse 2 561 1a 0 0 1b 0 Lower level

cardiovascular and
cerebrovascular
reactions

Renal transplant 8 3,114 1a 0 0 0 0 Medium level

failure

Acute rejection 2 2,176 1a 0 0 1b 0 Lower level

reaction

All-cause 4 2,699 1a 0 0 1b 0 Lower level

mortality rate
a
The description of randomized grouping, allocation concealment, and blinding in the included studies was unclear.
b
The sample size included in the study was small, the confidence interval was wide, and it crossed the invalid line.

exploring new biomarkers and personalized treatment approaches control group settings, consistent treatment doses and durations, and
could enhance the precision of lipid management strategies. comprehensive documentation of patient demographic characteristics
To enhance the comparability of future meta-analyses, more and other relevant variables. Such standardization will enable future
standardized clinical trials are needed in this field. These trials research to provide more reliable data, thereby better guiding clinical
should adhere to uniform design principles, including well-defined practice and policy development.

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Luo et al. 10.3389/fphar.2024.1440875

5 Conclusion administration, Methodology, Funding acquisition, Formal

Analysis, Data curation, Conceptualization.
The combination of statins and ezetimibe can better reduce lipid
levels in PKT patients, while PCSK9 inhibitors can lower the
incidence of adverse reactions and all-cause mortality in these Funding
patients, demonstrating high efficacy and safety. Therefore, they
have the potential for widespread clinical application. The author(s) declare that no financial support was received for
the research, authorship, and/or publication of this article.

Data availability statement

Conflict of interest
The original contributions presented in the study are included in
the article/Supplementary Material, further inquiries can be directed The authors declare that the research was conducted in the
to the corresponding author. absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.

Author contributions
Publisher’s note
BL: Writing–review and editing, Writing–original draft,
Visualization, Validation, Supervision, Software, Resources, All claims expressed in this article are solely those of the authors and
Project administration, Methodology, Investigation, Funding do not necessarily represent those of their affiliated organizations, or
acquisition, Formal Analysis, Data curation, Conceptualization. those of the publisher, the editors and the reviewers. Any product that
SZ: Visualization, Validation, Supervision, Software, Resources, may be evaluated in this article, or claim that may be made by its
Project administration, Methodology, Investigation, Funding manufacturer, is not guaranteed or endorsed by the publisher.
acquisition, Data curation, Conceptualization, Writing–review
and editing, Writing–original draft, Formal Analysis. XW:
Writing–review and editing, Validation, Formal Analysis, Data Supplementary material
curation. PG: Writing–review and editing, Validation, Formal
Analysis, Data curation. YH: Writing–review and editing, The Supplementary Material for this article can be found online
Validation, Formal Analysis, Data curation. WD: Writing–review at: https://www.frontiersin.org/articles/10.3389/fphar.2024.1440875/
and editing, Validation, Supervision, Resources, Project full#supplementary-material.

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