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 (sic)18 557 per life year gained and (sic)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. Pharmacogenetics and Genomics 21: 417-425 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

Association of blood pressure with decline in renal function and time until the start of renal replacement therapy in pre-dialysis patients: a cohort study

<p>Abstract</p> <p>Background</p> <p>To investigate whether high blood pressure accelerates renal function decline in patients with advanced chronic kidney disease (CKD), we studied the association of systolic (SBP) and diastolic blood pressure (DBP) with decline in renal function and time until the start of renal replacement therapy (RRT) in patients with CKD stages IV-V on pre-dialysis care.</p> <p>Methods</p> <p>In the PREPARE-1 cohort 547 incident pre-dialysis patients, referred as part of the usual care to outpatient clinics of eight Dutch hospitals, were included between 1999 and 2001 and followed until the start of RRT, mortality, or end of follow-up (January 1^st2008). Main outcomes were rate of decline in renal function, estimated as the slope of available eGFR measurements, and time until the start of RRT.</p> <p>Results</p> <p>A total of 508 patients, 57% men and median (IQR) age of 63 (50-73) years, were available for analyses. Mean (SD) decline in renal function was 0.35 (0.75) ml/min/1.73 m²/month. Every 10 mmHg increase in SBP or DBP resulted in an accelerated decline in renal function (adjusted additional decline 0.04 (0.02;0.07) and 0.05 (0.00;0.11) ml/min/1.73 m²/month respectively) and an earlier start of RRT (adjusted HR 1.09 (1.04;1.14) and 1.16 (1.05;1.28) respectively). Furthermore, patients with SBP and DBP above the BP target goal of < 130/80 mmHg experienced a faster decline in renal function (adjusted additional decline 0.31 (0.08;0.53) ml/min/1.73 m²/month) and an earlier start of RRT (adjusted HR 2.08 (1.25;3.44)), compared to patients who achieved the target goal (11%). Comparing the decline in renal function and risk of starting RRT between patients with only SBP above the target (≥ 130 mmHg) and patients with both SBP and DBP below the target (< 130/80 mmHg), showed that the results were almost similar as compared to patients with both SBP and DBP above the target (adjusted additional decline 0.31 (0.04;0.58) ml/min/1.73 m²/month and adjusted HR 2.24 (1.26;3.97)). Therefore, it seems that especially having SBP above the target is harmful.</p> <p>Conclusions</p> <p>In pre-dialysis patients with CKD stages IV-V, having blood pressure (especially SBP) above the target goal for CKD patients (< 130/80 mmHg) was associated with a faster decline in renal function and a later start of RRT.</p

ACE I/D polymorphism is associated with mortality in a cohort study of patients starting with dialysis

ACE I/D polymorphism is associated with mortality in a cohort study of patients starting with dialysis.BackgroundIn dialysis patients, only a few follow-up studies have addressed the relationship between the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene and mortality, but the available data are contradictory.MethodsA cohort of 453 consecutive patients starting dialysis between January 1999 and January 2002 and participating in a Dutch multicenter prospective study was examined. Patients who died within 3 months after the start of dialysis were excluded. Patients were followed until date of death or censoring in November 2003.ResultsThe ACE II, ID, and DD genotype frequencies were 24.3% (N = 110), 50.1% (N = 227), and 25.6% (N = 116). Besides a slightly higher number of Caucasians in the DD group, all other patient characteristics of the 3 ACE groups were similar at the start of dialysis. After adjustment for age, comorbidity, and ethnic background, patients with the ID and DD genotype showed an increased hazard ratio (HR) for all-cause mortality of 1.55 (95% CI 1.00-2.42) and 2.30 (95% CI 1.41-3.75), compared to patients with the II genotype. Slightly lower HRs were found for cardiovascular mortality. All groups of primary kidney disease showed a 2- to 3-fold increased adjusted HR for DD.ConclusionThe DD genotype identifies dialysis patients at an increased risk for mortality

Survival in dialysis patients is not different between patients with diabetes as primary renal disease and patients with diabetes as a co-morbid condition

On dialysis, survival among patients with diabetes mellitus is inferior to survival of non-diabetic patients. We hypothesized that patients with diabetes as primary renal disease have worse survival compared to patients with diabetes as a co-morbid condition and aimed to compare all-cause mortality between these patient groups. Data were collected from the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD), a multicenter, prospective cohort study in which new patients with end stage renal disease (ESRD) were monitored until transplantation or death. Patients with diabetes as primary cause of ESRD were compared with patients with diabetes as co-morbid condition and both of these patient groups were compared to patients without diabetes. Analysis was performed using Kaplan-Meier and Cox regression. Fifteen % of the patients had diabetic nephropathy as primary renal disease (N = 281); 6% had diabetes as co-morbid condition (N = 107) and 79% had no diabetes (N = 1465). During follow-up 42% of patients (N = 787) died. Compared to non-diabetic patients, mortality risk was increased for both patients with diabetes as primary renal disease HR: 1.9 (95% CI 1.6, 2.3) and for patients with diabetes as co-morbid condition HR: 1.7 (95% CI 1.3, 2.2). Mortality was not significantly higher in patients with diabetes as primary renal disease compared to patients with diabetes as co-morbid condition (HR 1.06; 95% CI 0.79, 1.43). This study in patients with ESRD showed no survival difference between patients with diabetes as primary renal disease and patients with diabetes as a co-morbid condition. Both conditions were associated with increased mortality risk compared to non-diabetic patient

Pre-dialysis patients' perceived autonomy, self-esteem and labor participation: associations with illness perceptions and treatment perceptions. A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Compared to healthy people, patients with chronic kidney disease (CKD) participate less in paid jobs and social activities. The aim of the study was to examine a) the perceived autonomy, self-esteem and labor participation of patients in the pre-dialysis phase, b) pre-dialysis patients' illness perceptions and treatment perceptions, and c) the association of these perceptions with autonomy, self-esteem and labor participation.</p> <p>Methods</p> <p>Patients (N = 109) completed questionnaires at home. Data were analysed using bivariate and multivariate analyses.</p> <p>Results</p> <p>The results showed that the average autonomy levels were not very high, but the average level of self-esteem was rather high, and that drop out of the labor market already occurs during the pre-dialysis phase. Positive illness and treatment beliefs were associated with higher autonomy and self-esteem levels, but not with employment. Multiple regression analyses revealed that illness and treatment perceptions explained a substantial amount of variance in autonomy (17%) and self-esteem (26%). The perception of less treatment disruption was an important predictor.</p> <p>Conclusions</p> <p>Patient education on possibilities to combine CKD and its treatment with activities, including paid work, might stimulate positive (realistic) beliefs and prevent or challenge negative beliefs. Interventions focusing on these aspects may assist patients to adjust to CKD, and ultimately prevent unnecessary drop out of the labor market.</p

Electrophysiological study of local/global processing in Williams syndrome

Persons with Williams syndrome (WS) demonstrate pronounced deficits in visuo-spatial processing. The purpose of the current study was to examine the preferred level of perceptual analysis in young adults with WS (n = 21) and the role of attention in the processing of hierarchical stimuli. Navon-like letter stimuli were presented to adults with WS and age-matched typical controls in an oddball paradigm where local and global targets could appear with equal probability. Participants received no explicit instruction to direct their attention toward a particular stimulus level. Behavioral and event-related potential (ERP) data were recorded. Behavioral data indicated presence of a global precedence effect in persons with WS. However, their ERP responses revealed atypical brain mechanisms underlying attention to local information. During the early perceptual analysis, global targets resulted in reduced P1 and enhanced N150 responses in both participant groups. However, only the typical comparison group demonstrated a larger N150 to local targets. At the more advanced stages of cognitive processing, a larger P3b response to global and local targets was observed in the typical group but not in persons with WS, who instead demonstrated an enhanced P3a to global targets only. The results indicate that in a perceptual task, adults with WS may experience greater than typical global-to-local interference and not allocate sufficient attentional resources to local information

Home Dialysis: A Dutch Perspective

For patients with end-stage renal disease who are not (yet) eligible for renal transplantation, treatment with dialysis is mandatory for survival. Home dialysis modalities (home hemodialysis or peritoneal dialysis) offer patients more flexibility compared with in-center treatment and have been advocated as the first choice in clinically stable patients. However, despite encouraging developments in dialysis systems that make the procedure easier, in many countries the proportion of patients using home dialysis, especially peritoneal dialysis, is decreasing. In Europe this decrease is most pronounced in the Netherlands and the United Kingdom. This evolution cannot be motivated by an inferiority of home dialysis modalities compared with in-center treatment, as all these modalities have been shown to generate similar results. Other, often non-medical, factors (such as reimbursement, social and logistic issues, and the experience of physicians and nurses with home dialysis) seem to be responsible for this developmen

Treatment with angiotensin II inhibitors and residual renal function in peritoneal dialysis patients

Many studies have shown the renoprotective effect of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) in patients with chronic kidney disease stages I-IV. Two randomized controlled trials (RCTs) showed a positive effect of AII inhibitors on residual glomerular filtration rate (rGFR) in peritoneal dialysis (PD) patients. However, these studies were small and were performed in a highly selected group of PD patients. Our aim was to confirm the above findings in a larger number of prospectively followed PD patients. First we analyzed the time course of decline of rGFR in 452 incident PD patients that were not anuric at the start of dialysis and that had structured follow-up data, with measurements at 3, 6, 12, 18, 24, 30, and 36 months after the start of dialysis. Changes in rGFR over time were analyzed with a linear mixed model for repeated measures. In addition, Cox regression models were used to estimate the risk of developing anuria. In a second approach, we aimed to repeat the above analyses in a selected group of patients that theoretically could have been randomized and therefore resembled the population studied in the 2 mentioned RCTs. In this group the follow-up was restricted to 1 year. 201 patients were treated with ACEi/ARBs and 251 did not take these drugs at the start of PD. More patients from the treated group had diabetes and used more antihypertensive medications. The time course of decline of rGFR was not different between the 2 groups over the 3 years of PD treatment (p = 0.52). Less than 25% of patients from each group became anuric and there was no difference in time to development of complete anuria between the treated and untreated groups. In the second approach, 130 patients were included: 37 were treated with ACEi/ARBs and 93 were not. Again, no difference was found between the 2 groups with respect to the rate of decline of rGFR and time of anuria development. Our findings are not in line with the results of previous RCTs. The biggest limitation of observational studies is the inability to avoid confounding by indication. However, a RCT in such a setting also does not give a reliable answer. Given all the benefits of ACEi/ARBs, the medications should not be withheld from PD patients. However, their renoprotective effects may often be overruled by other factors influencing the time course of rGF