Innovative Lipid Biomarkers and Long-Term Outcomes:studies in patients treated with renal replacement therapy and in the general population

Cardiovascular disease is the leading cause of mortality in the developed world. Atherosclerosis, the main driving factor behind cardiovascular disease, is largely influenced by lipids. Patients with a decreased kidney function, such as dialysis patients or patients who have undergone a kidney transplantation are at a particularly high risk of cardiovascular disease. Furthermore, they can develop atherosclerotic lesions in the (transplanted) kidney, leading to further function decline and eventually kidney failure. Low density lipoproteins (LDL), the ‘bad’ cholesterol, and triglycerides promote the formation of atherosclerotic plaques. High density lipoprotein (HDL), the ‘good’ cholesterol is able to break down atherosclerosis and thereby lowers the risk of cardiovascular disease. In this thesis this process was evaluated in dialysis patients, which showed that they have a decreased ability of HDL to perform this protective effect. Furthermore, a novel protective effect of HDL was described, namely the ability to lower inflammation. This protective effect indeed leads to a lower risk of cardiovascular disease in the general population. A different way of describing lipid abnormalities, by using a ratio of triglycerides to the HDL, is better at identifying patients who are at risk of cardiovascular disease of kidney disease. Furthermore, a risk score developed for cardiovascular disease is also able to predict kidney disease, which lends evidence to the fact that both processes are driven by atherosclerosis. In conclusion, this thesis identified novel biomarkers for atherosclerosis and shows how important close attention to lipid control is in both kidney disease patients and the general population

The triglyceride to HDL-cholesterol ratio and chronic graft failure in renal transplantation

BACKGROUND: Transplant vasculopathy (TV) is a major contributing factor to chronic graft failure in renal transplant recipients (RTR). TV lesions resemble atherosclerosis in several ways, and it is plausible to believe that some risk factors influence both atherosclerotic plaque formation and formation of TV. OBJECTIVE: The objective of this prospective longitudinal study was to determine if dyslipidemia reflected by the triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio is prospectively associated with death censored chronic graft failure in RTR. METHOD: 454 prospectively included RTR with a functioning graft for at least one year, were followed for a median of 7 years. RTR were matched based on propensity scores to avoid potential confounding and subsequently the association of the TG/HDL-C ratio with the endpoint chronic graft failure, defined as return to dialysis or re-transplantation, was investigated. RESULTS: Linear regression analysis showed that concentration of insulin, male gender, BMI and number of antihypertensives predict the TG/HDL-C ratio. Cox regression showed that the TG/HDL-C ratio is associated with chronic graft failure (HR = 1.43, 95%CI = 1.12-1.84, p = 0.005) in competing risk analysis for mortality. Interaction testing indicated that the relationship of the TG/HDL-C ratio with graft failure is stronger in subjects with a higher insulin concentration. CONCLUSION: Our results demonstrate that the TG/HDL-C ratio has the potential to act as a predictive clinical biomarker. Furthermore, there is a need for closer attention to lipid management in RTR in clinical practice with a focus on triglyceride metabolism. (c) 2021 National Lipid Association. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer.

Renal cell carcinoma (RCC) is increasing in incidence, and a complete cure remains elusive. While immune-checkpoint antibodies are promising, interferon-based immunotherapy has been disappointing. Tryptophan metabolism, which produces immunosuppressive metabolites, is enhanced in RCC. Here we show indolamine-2,3-dioxygenase-1 (IDO1) expression, a kynurenine pathway enzyme, is increased not only in tumor cells but also in the microenvironment of human RCC compared to normal kidney tissues. Neither kynurenine metabolites nor IDO inhibitors affected the survival or proliferation of human RCC or murine renal cell adenocarcinoma (RENCA) cells in vitro. However, interferon-gamma (IFNγ) induced high levels of IDO1 in both RCC and RENCA cells, concomitant with enhanced kynurenine levels in conditioned media. Induction of IDO1 by IFNα was weaker than by IFNγ. Neither the IDO1 inhibitor methyl-thiohydantoin-DL-tryptophan (MTH-trp) nor IFNα alone inhibited RENCA tumor growth, however the combination of MTH-trp and IFNα reduced tumor growth compared to IFNα. Thus, the failure of IFNα therapy for human RCC is likely due to its inability to overcome the immunosuppressive environment created by increased IDO1. Based on our data, and given that IDO inhibitors are already in clinical trials for other malignancies, IFNα therapy with an IDO inhibitor should be revisited for RCC

Statin use and incident cardiovascular events in renal transplant recipients

BACKGROUND: Statins achieve potent LDL lowering in the general population leading to a significant cardiovascular (CV) risk reduction. In renal transplant recipients (RTR) statins are included in treatment guidelines, however, conclusive evidence of improved cardiovascular outcomes has not been uniformly provided and concerns have been raised about simultaneous use of statins and the immunosuppressant cyclosporine. This study aimed to elucidate the effect of statins on a compound CV endpoint, comprised of ischaemic CV events and CV mortality in RTR, with subgroup analysis focussing on cyclosporine users. METHOD: 622 included RTR (follow‐up 5.4 years) were matched based on propensity scores and dichotomized by statin use. Survival analysis was conducted. RESULTS: Cox regression showed that statin use was not significantly associated with the compound CV endpoint in a fully adjusted model (HR = 0.81, 95% CI = 0.53‐1.24, P = .33). Subgroup analyses in RTR using cyclosporine revealed a strong positive association of statin use with the CV compound outcome in a fully adjusted model (HR = 6.60, 95% CI 1.75‐24.9, P = .005). Furthermore, statin use was positively correlated with cyclosporine trough levels (correlation coefficient 0.11, P = .04). CONCLUSION: In conclusion, statin use does not significantly decrease incident CV events in an overall RTR cohort, but is independently associated with CV‐specific mortality and events in cyclosporine using RTR, possibly due to a bilateral pharmacological interaction

The Framingham Risk Score Is Associated with Chronic Graft Failure in Renal Transplant Recipients

Predicting chronic graft failure in renal transplant recipients (RTR) is an unmet clinical need. Chronic graft failure is often accompanied by transplant vasculopathy, the formation of de novo atherosclerosis in the transplanted kidney. Therefore, we determined whether the 10-year Framingham risk score (FRS), an established atherosclerotic cardiovascular disease prediction module, is associated with chronic graft failure in RTR. In this prospective longitudinal study, 600 well-characterised RTR were followed for 10 years. The association with death-censored chronic graft failure (n = 81, 13.5%) was computed. An extended Cox model showed that each one percent increase of the FRS significantly increased the risk of chronic graft failure by 4% (HR: 1.04, p &lt; 0.001). This association remained significant after adjustment for potential confounders, including eGFR (HR: 1.03, p = 0.014). Adding the FRS to eGFR resulted in a higher AUC in a receiver operating curve (AUC = 0.79, p &lt; 0.001) than eGFR alone (AUC = 0.75, p &lt; 0.001), and an improvement in the model likelihood ratio statistic (67.60 to 88.39, p &lt; 0.001). These results suggest that a combination of the FRS and eGFR improves risk prediction. The easy to determine and widely available FRS has clinical potential to predict chronic graft failure in RTR.</p

High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events

Background:The role of high-density lipoprotein (HDL) function in cardiovascular disease represents an important emerging concept. The present study investigated whether HDL anti-inflammatory capacity is prospectively associated with first cardiovascular events in the general population.Methods:HDL anti-inflammatory capacity was determined as its ability to suppress TNF alpha (tumor necrosis factor alpha)-induced VCAM-1 (vascular cell adhesion molecule-1) mRNA expression in endothelial cells in vitro (results expressed as achieved percent reduction by individual HDL related to the maximum TNF alpha effect with no HDL present). In a nested case-control design of the PREVEND (Prevention of Renal and Vascular End Stage Disease) study, 369 cases experiencing a first cardiovascular event (combined end point of death from cardiovascular causes, ischemic heart disease, nonfatal myocardial infarction, and coronary revascularization) during a median of 10.5 years of follow-up were identified and individually matched to 369 controls with respect to age, sex, smoking status, and HDL cholesterol. Baseline samples were available in 340 cases and 340 matched controls.Results:HDL anti-inflammatory capacity was not correlated with HDL cholesterol or hsCRP (high-sensitivity C-reactive protein). HDL anti-inflammatory capacity was significantly lower in cases compared with controls (31.6% [15.7-44.2] versus 27.0% [7.4-36.1]; P0.05). When combining these 2 HDL function metrics in 1 model, both were significantly and independently associated with incident cardiovascular disease in a fully adjusted model (efflux: OR per 1 SD, 0.74; P=0.002; anti-inflammatory capacity: OR per 1 SD, 0.66; PConclusions:The HDL anti-inflammatory capacity, reflecting vascular protection against key steps in atherogenesis, was inversely associated with incident cardiovascular events in a general population cohort, independent of HDL cholesterol and HDL cholesterol efflux capacity. Adding HDL anti-inflammatory capacity to the Framingham risk score improves risk prediction.</p

High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events

Background: The role of high-density lipoprotein (HDL) function in cardiovascular disease represents an important emerging concept. The present study investigated whether HDL anti-inflammatory capacity is prospectively associated with first cardiovascular events in the general population. Methods: HDL anti-inflammatory capacity was determined as its ability to suppress TNF alpha (tumor necrosis factor alpha)-induced VCAM-1 (vascular cell adhesion molecule-1) mRNA expression in endothelial cells in vitro (results expressed as achieved percent reduction by individual HDL related to the maximum TNF alpha effect with no HDL present). In a nested case-control design of the PREVEND (Prevention of Renal and Vascular End Stage Disease) study, 369 cases experiencing a first cardiovascular event (combined end point of death from cardiovascular causes, ischemic heart disease, nonfatal myocardial infarction, and coronary revascularization) during a median of 10.5 years of follow-up were identified and individually matched to 369 controls with respect to age, sex, smoking status, and HDL cholesterol. Baseline samples were available in 340 cases and 340 matched controls. Results: HDL anti-inflammatory capacity was not correlated with HDL cholesterol or hsCRP (high-sensitivity C-reactive protein). HDL anti-inflammatory capacity was significantly lower in cases compared with controls (31.6% [15.7-44.2] versus 27.0% [7.4-36.1]; P0.05). When combining these 2 HDL function metrics in 1 model, both were significantly and independently associated with incident cardiovascular disease in a fully adjusted model (efflux: OR per 1 SD, 0.74; P=0.002; anti-inflammatory capacity: OR per 1 SD, 0.66; P Conclusions: The HDL anti-inflammatory capacity, reflecting vascular protection against key steps in atherogenesis, was inversely associated with incident cardiovascular events in a general population cohort, independent of HDL cholesterol and HDL cholesterol efflux capacity. Adding HDL anti-inflammatory capacity to the Framingham risk score improves risk prediction

Proteoglycan binding as proatherogenic function metric of apoB-containing lipoproteins and chronic kidney graft failure

Lipoprotein-proteoglycan binding is an early key event in atherosclerotic lesion formation and thus conceivably could play a major role in vasculopathy-driven chronic graft failure and cardiovascular mortality in renal transplant recipients. The present study investigated whether lipoproteinproteoglycan binding susceptibility (LPBS) of apoBcontaining lipoproteins and levels of the classical atherosclerosis biomarker LDL-C were associated with cardiovascular mortality (n = 130) and graft failure (n = 73) in 589 renal transplant recipients who were followed up from at least 1 year after transplantation for 9.5 years. At baseline, LPBS was significantly higher in patients who subsequently developed graft failure than in those with a surviving graft (1.68 +/- 0.93 vs. 1.46 +/- 0.49 nmol/mmol, P = 0.001). Cox regression analysis showed an association between LPBS and chronic graft failure in an age-and sex-adjusted model (hazard ratio: 1.45; 95% CI, 1.14-1.85; P = 0.002), but no association was observed with cardiovascular mortality. LDL-C levels were not associated with graft failure or cardiovascular mortality. This study shows that measurement of cholesterol retention outperformed the traditionally used quantitative parameter of LDL-C levels in predicting graft failure, suggesting a higher relevance of proatherogenic function than the quantity of apoBcontaining lipoproteins in chronic kidney graft failure.Peer reviewe