Identification of endophenotypes supporting outcome prediction in hemodialysis patients based on mechanistic markers of statin treatment.

Background: Statins are widely used to reduce the risk of cardiovascular disease (CVD). Patients with end-stage renal disease (ESRD) on hemodialysis have significantly increased risk of developing CVD. Statin treatment in these patients however did not show a statistically significant benefit in large trials on a patient cohort level. Methods: We generated gene expression profiles for statins to investigate the impact on cellular programs in human renal proximal tubular cells and mesangial cells in-vitro. We subsequently selected biomarkers from key statin-affected molecular pathways and assessed these biomarkers in plasma samples from the AURORA cohort, a double-blind, randomized, multi-center study of patients on hemodialysis or hemofiltration that have been treated with rosuvastatin. Patient clusters (phenotypes) were created based on the identified biomarkers using Latent Class Model clustering and the associations with outcome for the generated phenotypes were assessed using Cox proportional hazards regression models. The multivariable models were adjusted for clinical and biological covariates based on previously published data in AURORA. Results: The impact of statin treatment on mesangial cells was larger as compared with tubular cells with a large overlap of differentially expressed genes identified for atorvastatin and rosuvastatin indicating a predominant drug class effect. Affected molecular pathways included TGFB-, TNF-, and MAPK-signaling and focal adhesion among others. Four patient clusters were identified based on the baseline plasma concentrations of the eight biomarkers. Phenotype 1 was characterized by low to medium levels of the hepatocyte growth factor (HGF) and high levels of interleukin 6 (IL6) or matrix metalloproteinase 2 (MMP2) and it was significantly associated with outcome showing increased risk of developing major adverse cardiovascular events (MACE) or cardiovascular death. Phenotype 2 had high HGF but low Fas cell surface death receptor (FAS) levels and it was associated with significantly better outcome at 1 year. Conclusions: In this translational study, we identified patient subgroups based on mechanistic markers of statin therapy that are associated with disease outcome in patients on hemodialysis.

Levels of Procollagen Type I C-Terminal Pro-Peptide and Galectin-3, Arterial Stiffness Measured By Pulse Wave Velocity, and Cardiovascular Morbidity and Mortality in 44 Patients 2 Years After Kidney Transplantation.

BACKGROUND Cardiovascular (CV) mortality remains high despite the improvement of kidney function after kidney transplantation. In heart failure (HF), high concentrations of biomarkers of fibrosis, related to cardiac and/or vascular impairment, are associated with CV outcomes, but their significance in kidney transplantation is still unclear. Our aim was to investigate the association of procollagen type I C-terminal pro-peptide (PICP) and galectin-3 (Gal-3), markers of fibrosis, with arterial stiffness measured by pulse wave velocity (PWV) and CV morbi-mortality in kidney transplantation recipients from the prospective monocenter TRANSARTE study (Transplantation and Arteries), which compared the evolution of arterial stiffness in transplanted patients and patients remained on dialysis. MATERIAL AND METHODS PICP and Gal-3 were measured at 2 years after transplantation in 44 kidney transplantation patients. Spearman's rank-order correlation analysis was conducted to assess the relationship between biomarkers and PWV. Association of biomarkers with CV morbi-mortality was evaluated using Cox regression analysis adjusted for age, renal function, and PWV. RESULTS There was no significant correlation between PWV and PICP (r=-0.16, P=0.3) or Gal-3 (r=0.03, P=0.85). Gal-3, after adjusting for key prognostic factors, including PWV, was significantly associated with CV morbi-mortality [HR (95% CI)=4.30 (1.01-18.22), P=0.048], whereas PICP was not significantly associated with outcome. CONCLUSIONS In multivariable adjusted analysis, elevated Gal-3 concentrations were associated with CV morbi-mortality in kidney transplantation patients, whereas PICP was not. As Gal-3 was not related to PWV, other sources of fibrosis (eg, cardiac fibrosis) may be underlying the prognostic value of Gal-3 in kidney transplantation.

Association between Long-Term Change in Arterial Stiffness and Cardiovascular Outcomes in Kidney Transplant Recipients: Insights from the TRANSARTE Study.

(1) Background: Increased arterial stiffness is associated with cardiovascular (CV) diseases in end-stage renal disease (ESRD) patients, and CV mortality remains higher in kidney transplantation (KT) recipients compared to in the general population. KT is associated with an improvement in arterial stiffness in the early post-transplant period, followed by a potential re-worsening in the late period. In a cohort of KT patients, we evaluated the associations of pulse-wave velocity (PWV) measured at different time-points (pre-transplant, and early and late post-transplant periods) with CV morbi-mortality, as well as the evolution between these measurements with CV morbi-mortality. (2) Methods: Forty KT recipients with a 10-year follow-up were included. The association of PWV with CV events was assessed with multivariable cox analysis. Backward linear regressions were conducted to identify the determinants of PWV at 1 year and those of the long-term evolution of PWV after KT (delta PWV at 1 year­latest PWV). (3) Results: The absence of arterial stiffening during the long-term follow-up after KT is associated with a lower CV outcome rate (HR for the delta PWV = 0.76 (0.58−0.98), p = 0.036). Age at KT is associated with the worsening of arterial stiffness in the late post-transplantation period (ß for the delta PWV = −0.104, p = 0.031). A high PWV at 1 year was associated with a potential for recovery during follow-up (ß = 0.744, p < 0.0001). (4) Conclusions: The absence of PWV worsening in the late post-transplantation period was significantly associated with a lower risk of CV events, whereas early changes in PWV were not. Finding an intervention capable of reducing long-term PWV could improve the prognosis of KT recipients.

Serum markers of fibrosis, cardiovascular and all-cause mortality in hemodialysis patients: the AURORA trial.

BACKGROUND: Biomarkers of fibrosis are associated with outcome in several cardiovascular diseases. However, their relevance to chronic kidney disease and dialysis is uncertain, as it remains unclear how the kidneys and the dialysis procedure itself affect their elimination and degradation. We aimed to investigate the relationship of the blood levels of two markers associated with fibrosis: procollagen type I C-terminal pro-peptide (PICP) and galectin-3 (Gal-3) with mortality in dialysis patients. METHODS: Procollagen type I C-terminal pro-peptide and galectin-3 were measured at baseline in 2773 patients enrolled in the AURORA trial, investigating the effect of rosuvastatin on cardiovascular outcomes, in patients on hemodialysis, and their interaction with CV death or all-cause mortality using survival models. The added prognostic value of these biomarkers was assessed by the net reclassification improvement (NRI). RESULTS: The median follow-up period was 3.8 years. Blood concentrations of PICP and Gal-3 were significantly associated with CV death [adjusted HR per 1 SD = 1.11 (1.02-1.20) and SD = 1.20 (1.10-1.31), respectively] and all-cause mortality (all adjusted p < 0.001). PICP and Gal-3 had a synergistic effect with regard to CV death and all-cause mortality (interaction p = 0.04 and 0.01, respectively). Adding PICP, Gal-3 and their interaction on top of clinical and biological covariates, resulted in significantly improved prognostic accuracy NRI = 0.080 (0.019-0.143) for CV death. CONCLUSION: In dialysis patients, concomitant increase in PICP and Gal-3 concentrations are associated with higher rates of CV death. These results suggest that concomitantly raised PICP and Gal-3 may reflect an activated fibrogenesis relevant to risk stratification in dialysis, raising the hypothesis that anti-fibrotic therapy may be beneficial for cardiovascular protection in such patients.