We found that in stable KTRs, higher remnant cholesterol level is associated with an increased risk of CVD and all-cause mortality events in our large multicenter long-term KTR cohort after adjustments for the above covariates. These associations do not appear to be confounded by LDL and HDL cholesterol, although HDL seems to have a protective effect and decreased risk when adjusted for. LDL seems to play an important role in remnant cholesterol and CVD risk. Our findings are important, as many KTRs receive less-aggressive CVD risk factor management than would be expected given their underlying comorbid burden.
To our knowledge, we are the first to demonstrate the relationship among elevated remnant cholesterol levels and the risk of CVD events and all-cause mortality in RTRs. Currently LDL cholesterol is the target for pharmacotherapy in transplant patients and not triglyceride-rich lipoprotein such as remnant cholesterol. Currently there are no randomized clinical trials evaluating remnant cholesterol treatment targets in KTRs. There also seems to be a lack of information from large multicenter randomized trials as to whether reducing remnant cholesterol in KTRs will reduce the CVD risk, all-cause mortality and graft failure outcomes. However, evidence for increased triglyceride-rich lipoproteins as causal risk factors for CVD and all-cause mortality is emerging.[12–17] We believe that graft loss is not a confounder of the mortality outcomes but rather a mediator in the causal pathway. An observational study by Pilmore et al. examining extreme nonfasting remnant cholesterol versus extreme LDL cholesterol found only extreme nonfasting remnant cholesterol to be stepwise associated with increased all-cause mortality in the general population. Similar observational results showed a causal association between increased concentrations of nonfasting triglycerides (a marker of increased remnant cholesterol) and all-cause mortality.[14,15] Our study also showed that statin use was associated with reduced mortality rates in a large cohort of KTRs. Previous trials have consistently demonstrated that statins reduce cardiovascular morbidity and mortality in the general population; however, in renal patients—especially in KTRs—the beneficial effects of statins are less well established.[18,19]
The biological mechanisms that explain the results are the following: remnant cholesterol is the cholesterol content of the triglyceride-rich lipoproteins composed of VLDL and IDL in the fasting state and of these two lipoproteins together with chylomicron remnants in the nonfasting state. Recent studies indicated that the atherogenicity of chylomicron remnants is also strong and chylomicron remnants are contained in atherosclerotic plaque as VLDL remnants and these atherogenic remnants in patients with advanced CKD and kidney transplant have major adverse consequences. By limiting the reuptake of lipids in the adipocytes, downregulation of lipoprotein receptors and lipase contributes to the accelerated progression of reduced renal ability, especially in renal transplant patients. Additionally, oxidized LDL binding and other phospholipids to the receptors cause a cascading event that releases pro-inflammatory cytokines that contribute to the development of inflammation associated with chronic kidney disease. Therefore the circulating oxidized lipoprotein remnants disseminate and sustain the flames of oxidative stress throughout the body by initiating a lipid peroxidation chain reaction.[24,25] In this context, oxidized lipids and lipoproteins are both the cause and consequence of oxidative stress that could play a role in CVD and total mortality events.
We acknowledge the strengths of the study. First, the robust sample size of the FAVORIT cohort, ascertainment of outcome events and measurement of the laboratory values were valuable in the study. There are also limitations. One limitation in the study included the fact that trial participants were excluded for missing remnant cholesterol levels, although this was uncommon. Compared with the general CKD population, our study may have some limitations in terms of generalizability because of restriction to KTRs. Additionally, we lack information on baseline coronary artery disease, duration of dialysis and acute transplant rejection that would enhance our understanding of those who are at risk at baseline. Some caution is warranted when interpreting our statin results. Because our study patients were not randomly allocated to statin treatment, the possibility of confounding by indication must be considered due to the possibility that those with higher CVD risk are more than likely prescribed statins, causing bias within the statin group. Furthermore, the data are purely observational, based on a calculation of remnant cholesterol, and cannot address directly whether lowering remnant cholesterol concentrations would favorably affect any of the outcomes studied. The calculations of remnant cholesterol include both HDL and LDL, therefore we cannot directly put all three within the model.
In conclusion, in a large cohort of patients with kidney transplants followed for 4 years, we found that baseline levels of remnant cholesterol were highly associated with CVD and all-cause mortality. These prospective observations should be confirmed by large randomized controlled intervention trials in order to determine the clinical impact of remnant cholesterol reduction on CVD and all-cause mortality outcomes in stable KTRs.
We would like to acknowledge the tremendous contributions of the participants in the study and the contributions of the doctors, nurses and administrative staff in the hospitals and clinical centers in Brazil, Canada and the USA who assisted with the trial.
The FAVORIT trial is supported by cooperative agreement U01-DK61700 from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. Funders of this study did not have any role in study design; collection, analysis and interpretation of data; writing the article; or the decision to submit the article for publication.
Nephrol Dial Transplant. 2022;37(2):382-389. © 2022 Oxford University Press