Using a genetic, observational study as a strategy to estimate the potential cost-effectiveness of pharmacological CCR5 blockade in dialysis patients.

BACKGROUND AND OBJECTIVE: Randomized clinical trials are expensive and time consuming. Therefore, strategies are needed to prioritise tracks for drug development. Genetic association studies may provide such a strategy by considering the differences between genotypes as a proxy for a natural, lifelong, randomized at conception, clinical trial. Previously an association with better survival was found in dialysis patients with systemic inflammation carrying a deletion variant of the CC-chemokine receptor 5 (CCR5). We hypothesized that in an analogous manner, pharmacological CCR5 blockade could protect against inflammation-driven mortality and estimated if such a treatment would be cost-effective. METHODS: A genetic screen and treat strategy was modelled using a decision-analytic Markov model, in which patients were screened for the CCR5 deletion 32 polymorphism and those with the wild type and systemic inflammation were treated with pharmacological CCR5 blockers. Kidney transplantation and mortality rates were calculated using patient level data. Extensive sensitivity analyses were performed. RESULTS: The cost-effectiveness of the genetic screen and treat strategy was &OV0556;18 557 per life year gained and &OV0556;21 896 per quality-adjusted life years gained. Concordance between the genetic association and pharmacological effectiveness was a main driver of cost-effectiveness. Sensitivity analyses showed that even a modest effectiveness of pharmacological CCR5 blockade would result in a treatment strategy that is good value for money. CONCLUSION: Pharmacological blockade of the CCR5 receptor in inflamed dialysis patients can be incorporated in a potentially cost-effective screen and treat programme. These findings provide formal rationale for clinical studies. This study illustrates the potential of genetic association studies for drug development, as a source of Mendelian randomized evidence from an observational setting.

Subjective global assessment of nutritional status is strongly associated with mortality in chronic dialysis patients.

BACKGROUND: The subjective global assessment of nutritional status (SGA) is used to assess the nutritional status of chronic dialysis patients, but longitudinal data in relation to mortality risk are lacking. OBJECTIVE: Our objective was to study the long-term and time-dependent associations of the SGA with mortality risk in chronic dialysis patients. DESIGN: In a prospective, longitudinal, observational, multicenter study of incident dialysis patients, the 7-point SGA [7 = normal nutritional status; 1 = severe protein-energy wasting (PEW)] was assessed 3 and 6 mo after the start of dialysis and subsequently every 6 mo during 7 y of follow-up. With Cox regression analysis, we calculated hazard ratios (HRs) of the baseline and time-dependent SGA measurements, adjusted for age, sex, treatment modality, primary kidney diseases, and comorbidity. RESULTS: In total, 1601 patients were included [mean (+/-SD) age: 59 +/- 15 y; 61% men; 23% with moderate PEW (SGA(4-5)), and 5% with severe PEW (SGA(1-3))]. There was a dose-dependent trend of the 7-point SGA with mortality. Compared with a normal nutritional status at baseline, SGA(4-5) (HR: 1.6; 95% CI: 1.3, 1.9) and SGA(1-3) (HR: 2.1; 95% CI: 1.5, 2.8) were associated with an increase in 7-y mortality. Time-dependently, these associations were stronger: SGA(4-5) (HR: 2.1; 95% CI: 1.7, 2.5) and SGA(1-3) (HR: 5.0; 95% CI: 3.8, 6.5). CONCLUSIONS: In dialysis patients, PEW at baseline assessed with SGA was associated with a 2-fold increased mortality risk in 7 y of follow-up. Time-dependently, this association was even stronger, which indicated that PEW was associated with a remarkably high risk of short-term mortality. These data imply that the 7-point SGA may validly distinguish different degrees of PEW associated with increasing risks of mortality.

Association between a self-rated health question and mortality in young and old dialysis patients: a cohort study.

BACKGROUND: Self-rated health (SRH) has been shown to predict mortality in large community-based studies; however, large clinical-based studies of this topic are rare. We assessed whether an SRH item predicts mortality in a large sample of incident dialysis patients beyond sociodemographic, disease, and clinical measures and possible age interaction. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,443 predominantly white patients from 38 dialysis centers in The Netherlands participating in the Netherlands Cooperative Study on the Adequacy of Dialysis-2 between 1997 and 2004. PREDICTOR: SRH score completed at 3 months after the start of dialysis therapy (baseline). OUTCOMES & MEASUREMENTS: Cox proportional hazards model estimated the association between SRH and all-cause mortality. Interaction of SRH with age (<65 and >/=65 years) was examined in an additive model. RESULTS: Mean age of patients was 59.6 +/- 14.8 years, with 61% men and 69% married/living together. Mean follow-up was 2.7 +/- 1.8 years. Deaths per SRH group in the multivariate analyses sample: excellent/very good (9 of 63 patients; 14.3%), good (148 of 473 patients; 31.3%), fair (194 of 508 patients; 38.2%), and poor (45 of 71 patients; 63.4%). Patients with poor, fair, or good health ratings had a greater mortality risk than those with excellent/very good health ratings (adjusted hazard ratio [HR(adj)], 3.56; 95% confidence interval [CI], 1.71 to 7.42; HR(adj), 2.09; 95% CI, 1.06 to 4.12; HR(adj), 1.87; 95% CI, 0.95 to 3.70, respectively) independent of a range of risk factors. No age interaction with SRH was found. LIMITATIONS: Although the SRH-mortality association remained strong despite extensive adjustments, unknown residual confounding could still exist. CONCLUSION: SRH is an independent predictor of mortality in incident dialysis patients. Patients with poor SRH in both age strata had a significantly increased risk of mortality even after controlling for demographic and clinical confounders. Patient self-assessment of health can be an invaluable and economical complement to clinical measures in risk assessment.