Time-dependent impact of immunosuppressant regimens on cardiovascular outcomes in kidney transplant recipients: a nationwide cohort study

Abstract

Objectives: We aimed to evaluate the effect of different immunosuppressive regimens on the risk of major adverse cardiovascular events (MACEs) in kidney transplant recipients (KTRs).

Methods: This retrospective cohort study used nationwide claims data from the Korean Health Insurance Review and Assessment Service from between 2010 and 2021. Immunosuppressive medications were analyzed as time-dependent variables, and the primary outcome was MACEs, defined as a composite of myocardial infarction, coronary revascularization, ischemic stroke, and all-cause mortality.

Results: A total of 8,056 KTRs were included in the analysis, with significant risk factors for MACEs identified as male sex, older age, longer dialysis duration, lower economic status, and greater comorbidity. At the time of the kidney transplant, 86.7% of the KTRs were administered standard triple therapy, after which various immunosuppressive regimens, including sirolimus-inclusive regimens, were employed. The risk of MACE was lower or comparable in KTRs standard triple therapy than in those receiving most other immunosuppressive regimens. However, corticosteroid withdrawal was associated with a significant reduction in cardiovascular risk, particularly in KTRs with preexisting diabetes or dyslipidemia.

Conclusion: These findings suggest that early consideration should be given to minimizing steroid use in KTRs with dyslipidemia or diabetes to optimize cardiovascular outcomes.

Keywords: cardiovascular outcomes; comorbidity; immunosuppressive agents; kidney transplantation; time-dependent analysis.

FIGURE 1

Study timeline and design. Dialysis duration and modality were analyzed using all available data prior to the Index date Abbreviation: KT, kidney transplant; CCI, charlson comorbidity index; SRL, sirolimus; CNI, calcineurin inhibitor; AM, antimetabolite; STR, corticosteroid; statin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

FIGURE 2

Study cohort selection process. Abbreviation: KTRs, kidney transplant recipients; CVD, cardiovascular disease; MACE, major adverse cardiovascular events; mTOR, mammalian target of rapamycin.

FIGURE 3

Trends in immunosuppressive regimen use among kidney transplant recipients over 10 years. This figure illustrates the percentage of kidney transplant recipients receiving various immunosuppressive regimens over a 10-year period following kidney transplant. The solid line represents CNI + AM + STR, the dashed line indicates CNI + AM, the solid line with circular markers shows CNI + STR, the dashed line with circular markers denotes SRL-inclusive regimens, the solid line with triangular markers reflects patients on no medication, the dashed line with triangular markers represents CNI alone, and the solid line with square markers depicts AM + STR. The x-axis represents the number of years after kidney transplant and the y-axis indicates the percentage of kidney transplant recipients on each specific regimen. Abbreviations: SRL, sirolimus; CNI, calcineurin inhibitor; AM, antimetabolite; STR, corticosteroid; KT, kidney transplant; KTR, kidney transplant recipient.

FIGURE 4

Incidence rate and hazard ratio of MACE according to immunosuppressive regimens. Each immunosuppressive regimen is represented by four types of immunosuppressive medication (SRL, CNI, AM, STR). incidence rates are expressed as the number of events per 1,000 person-years. Hazard ratios were adjusted for sex, age, transplant year, type of insurance, dialysis duration, donor type, presence or absence of desensitization, drugs used in induction therapy, CCI, underlying disease. Forest plot illustrating hazard ratios for major adverse cardiovascular events. The x-axis is presented on a natural log scale. Horizontal lines represent the 95% confidence intervals. Abbreviations: SRL, sirolimus; CNI, calcineurin inhibitor; AM, antimetabolite; STR, corticosteroid; PY, person-year; IR, incidence rate; HR, hazard ratio; CI, confidence interval.

FIGURE 5

Subgroup analysis of major adverse cardiovascular events based on the presence or absence of pre-transplant diabetes and dyslipidemia according to immunosuppressive regimens. Each immunosuppressive regimen is represented by four types of immunosuppressive medication (SRL, CNI, AM, STR). Hazard ratios were adjusted for sex, age, transplant year, type of insurance, dialysis duration, donor type, presence or absence of desensitization, drugs used in induction therapy, CCI, underlying disease. Forest plot illustrating hazard ratios for major adverse cardiovascular events. The x-axis is presented on a natural log scale. Horizontal lines represent the 95% confidence intervals. (−) indicates the absence, and (+) indicates the presence of comorbidities. The standard regimen refers to triple therapy consisting of CNI, AM, and STR. Abbreviations: DM, diabetes; DLP, dyslipidemia; SRL, sirolimus; CNI, calcineurin inhibitor; AM, antimetabolite; STR, corticosteroid; aHR, adjusted hazard ratio; CI, confidence interval.