Vianda S. Stel

Risk prediction models

Prognostic research focuses on the prediction of the future course of a given disease in probability terms. Prognostication is performed by clinical decision makers by using risk prediction models that allow us to estimate the probability that a specific event occurs in a given patient over a predefined time period conditional on prognostic factors (predictors). Before application in clinical practice, risk prediction models should be properly validated by assessing their discrimination and calibration, or explained variation. Reclassification analyses allow us to evaluate the gain in risk prediction by using a new model compared with an established one. We discuss the concepts of developing and validating risk prediction models by means of two examples, the Framingham risk calculator for prediction of coronary heart disease (CHD), and the recently published Renal Risk Score to predict progression of chronic kidney disease (CKD).

Residual renal function at the start of dialysis and clinical outcomes

BACKGROUND This study evaluates the association between estimated GFR (eGFR) at the start of dialysis and mortality within Europe. METHODS Renal registries participating in the ERA-EDTA Registry were asked to provide data on serum creatinine recorded 0-4 weeks before the start of dialysis in incident dialysis patients in 1999 and 2003. Within this cohort study, data were available in 11 472 patients from nine national or regional European renal registries. Cox regression analyses were performed to examine the association between GFR estimated by the four-variable MDRD equation (eGFR) and all-cause mortality, using a follow-up through 31 December 2005. RESULTS In the 2003 data, the mean eGFR was 8.6 ml/min/1.73 m(2). The unadjusted survival analyses showed that an increase in eGFR of 1 ml/min/1.73 m(2) was associated with a higher mortality risk (HR = 1.03; 95% CI: 1.03-1.04) that remained similar after adjustment for age, gender, primary renal disease, treatment modality, country and comorbidity. The findings were consistent across gender, treatment modalities, geographical regions and time periods (2003 versus 1999), but the association between a higher eGFR at the start of dialysis and mortality was the strongest in the youngest age groups and in patients with glomerulonephritis. Analyses at centre level showed that a 10% increase in the percentage of patients starting dialysis at high eGFR levels (>or=10.5 ml/min) was associated with a 22% higher mortality risk (HR = 1.22; 95% CI: 1.18-1.26). CONCLUSIONS This European study showed that a higher eGFR at the start of dialysis was associated with a higher mortality risk. However, an answer to the question when to start dialysis needs to come from randomized controlled trials.

CKD Prevalence Varies across the European General Population

CKD prevalence estimation is central to CKD management and prevention planning at the population level. This study estimated CKD prevalence in the European adult general population and investigated international variation in CKD prevalence by age, sex, and presence of diabetes, hypertension, and obesity. We collected data from 19 general-population studies from 13 European countries. CKD stages 1-5 was defined as eGFR<60 ml/min per 1.73 m(2), as calculated by the CKD-Epidemiology Collaboration equation, or albuminuria >30 mg/g, and CKD stages 3-5 was defined as eGFR<60 ml/min per 1.73 m(2) CKD prevalence was age- and sex-standardized to the population of the 27 Member States of the European Union (EU27). We found considerable differences in both CKD stages 1-5 and CKD stages 3-5 prevalence across European study populations. The adjusted CKD stages 1-5 prevalence varied between 3.31% (95% confidence interval [95% CI], 3.30% to 3.33%) in Norway and 17.3% (95% CI, 16.5% to 18.1%) in northeast Germany. The adjusted CKD stages 3-5 prevalence varied between 1.0% (95% CI, 0.7% to 1.3%) in central Italy and 5.9% (95% CI, 5.2% to 6.6%) in northeast Germany. The variation in CKD prevalence stratified by diabetes, hypertension, and obesity status followed the same pattern as the overall prevalence. In conclusion, this large-scale attempt to carefully characterize CKD prevalence in Europe identified substantial variation in CKD prevalence that appears to be due to factors other than the prevalence of diabetes, hypertension, and obesity.

An update on renal replacement therapy in Europe: ERA–EDTA Registry data from 1997 to 2006

BACKGROUND Recent studies have indicated a stabilization in the incidence rates of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in a number of European countries. The aim of this study was to provide an update on the incidence, prevalence and outcomes of RRT in Europe over the past decade. METHODS Nineteen European national or regional renal registries with registry data from 1997 to 2006 participated in the study. Incidence and prevalence trends were analysed with Poisson and Joinpoint regression. Cox regression methods were used to examine patient survival. RESULTS The total adjusted incidence rate of RRT for ESRD increased from 109.9 per million population (pmp) in 1997 to 119.7 pmp in 2000, i.e. an average annual percentage change (AAPC) of 2.9% (95% CI 2.1-3.8%). Thereafter, the incidence increased at a much lower rate to 125.4 pmp in 2006 [AAPC 0.6% (95% CI 0.3-0.8%)]. This change in the trend of the incidence of RRT was largely due to a stabilization in the incidence rates of RRT for females aged 65-74 years, males aged 75-84 years and patients receiving RRT for ESRD due to hypertension/renal vascular disease. The overall adjusted prevalence in Europe continued to increase linearly at 2.7% per year. Between the periods 1997-2001 and 2002-2006, the risk of death decreased for all treatment modalities, with the most substantial improvement in patients starting peritoneal dialysis [19% (95% CI 15-22%)] and in patients receiving a kidney transplant [17% (95% CI 11-23%)]. CONCLUSION This European study shows that the annual rise of the overall incidence rate of RRT for ESRD has diminished and that in several age groups the incidence rates have now stabilized. The survival of dialysis patients and kidney transplant recipients has continued to improve.

Renal replacement therapy in Europe: a summary of the 2012 ERA-EDTA Registry Annual Report

Background This article summarizes the 2012 European Renal Association—European Dialysis and Transplant Association Registry Annual Report (available at www.era-edta-reg.org) with a specific focus on older patients (defined as ≥65 years). Methods Data provided by 45 national or regional renal registries in 30 countries in Europe and bordering the Mediterranean Sea were used. Individual patient level data were received from 31 renal registries, whereas 14 renal registries contributed data in an aggregated form. The incidence, prevalence and survival probabilities of patients with end-stage renal disease (ESRD) receiving renal replacement therapy (RRT) and renal transplantation rates for 2012 are presented. Results In 2012, the overall unadjusted incidence rate of patients with ESRD receiving RRT was 109.6 per million population (pmp) (n = 69 035), ranging from 219.9 pmp in Portugal to 24.2 pmp in Montenegro. The proportion of incident patients ≥75 years varied from 15 to 44% between countries. The overall unadjusted prevalence on 31 December 2012 was 716.7 pmp (n = 451 270), ranging from 1670.2 pmp in Portugal to 146.7 pmp in the Ukraine. The proportion of prevalent patients ≥75 years varied from 11 to 32% between countries. The overall renal transplantation rate in 2012 was 28.3 pmp (n = 15 673), with the highest rate seen in the Spanish region of Catalonia. The proportion of patients ≥65 years receiving a transplant ranged from 0 to 35%. Five-year adjusted survival for all RRT patients was 59.7% (95% confidence interval, CI: 59.3–60.0) which fell to 39.3% (95% CI: 38.7–39.9) in patients 65–74 years and 21.3% (95% CI: 20.8–21.9) in patients ≥75 years.

Competing risks analyses: objectives and approaches.

Studies in cardiology often record the time to multiple disease events such as death, myocardial infarction, or hospitalization. Competing risks methods allow for the analysis of the time to the first observed event and the type of the first event. They are also relevant if the time to a specific event is of primary interest but competing events may preclude its occurrence or greatly alter the chances to observe it. We give a non-technical overview of competing risks concepts for descriptive and regression analyses. For descriptive statistics, the cumulative incidence function is the most important tool. For regression modelling, we introduce regression models for the cumulative incidence function and the cause-specific hazard function, respectively. We stress the importance of choosing statistical methods that are appropriate if competing risks are present. We also clarify the role of competing risks for the analysis of composite endpoints.

Global variation in renal replacement therapy for end-stage renal disease

BACKGROUND Incidence rates of renal replacement therapy (RRT) for end-stage renal disease vary considerably worldwide. This study examines the independent association between the general population, health care system and renal service characteristics and RRT incidence rates. METHODS RRT incidence data (2003-2005) were obtained from renal registries; general population age and health and macroeconomic indices were collected from secondary sources. Renal service organization and resource data were obtained through interviews and questionnaires. Linear regression models were built to establish the factors independently associated with RRT incidence, stratified by the Human Development Index where required. False discovery rate (FDR) correction was adjusted for multiple testing. RESULTS Across the 46 countries (population 1.25 billion), RRT incidence rates ranged from 12 to 455 (median 130) per million population. Gross domestic product (GDP) per capita [incidence rate ratio (IRR): 1.02 per

GFR at Initiation of Dialysis and Mortality in CKD: A Meta-analysis

1000 increase, P(FDR) = 0.047], percentage of GDP spent on health care (IRR: 1.11 per % increase, P(FDR) = 0.006) and dialysis facility reimbursement rate relative to GDP (IRR: 0.76 per GDP per capita-sized increase in reimbursement rate, P(FDR) = 0.007) were independently associated with RRT incidence. In more developed countries, the private for-profit share of haemodialysis facilities was also associated with higher incidence (IRR: 1.009 per % increase, P(FDR) = 0.003). CONCLUSIONS Macroeconomic and renal service factors are more often associated with RRT incidence rates than measured demographic or general population health status factors.

Effects of comorbid and demographic factors on dialysis modality choice and related patient survival in Europe

BACKGROUND The proportion of patients with advanced chronic kidney disease (CKD) initiating dialysis therapy at a higher glomerular filtration rate (GFR) has increased during the past decade. Recent data suggest that higher GFR may be associated with increased mortality. STUDY DESIGN A meta-analysis of cohort studies and trials. SETTING & POPULATION Patients with advanced CKD. SELECTION CRITERIA FOR STUDIES We performed a systematic literature search in MEDLINE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, American Society of Nephrology abstracts, and bibliographies of retrieved articles to identify studies reporting on GFR at dialysis therapy initiation and mortality. PREDICTOR Estimated or calculated GFR at dialysis therapy initiation. OUTCOME Pooled adjusted hazard ratio (HR) of continuous GFR for all-cause mortality. RESULTS 16 cohort studies and 1 randomized controlled trial were identified (n = 1,081,116). By meta-analysis restricted to 15 cohorts (n = 1,079,917), higher GFR at dialysis therapy initiation was associated with a higher pooled adjusted HR for all-cause mortality (1.04; 95% CI, 1.03-1.05; P < 0.001). However, there was significant heterogeneity (I(2) = 97%; P < 0.001). The association persisted among the 9 cohorts that adjusted analytically for nutritional covariates (HR, 1.03; 95% CI, 1.02-1.04; P < 0.001; residual I(2) = 97%). The highest mortality risk was observed in hemodialysis cohorts (HR, 1.05; 95% CI, 1.02-1.08; P < 0.001), whereas there was no association between GFR and mortality in peritoneal dialysis cohorts (HR, 1.04; 95% CI, 0.99-1.08, P = 0.1; residual I(2) = 98%). Finally, higher GFR was associated with a lower mortality risk in cohorts that calculated GFR (HR, 0.80; 95% CI, 0.71-0.91; P = 0.003), contrasting with a higher mortality risk in cohorts that estimated GFR (HR, 1.04; 95% CI, 1.03-1.05; P < 0.001; residual I(2) = 97%). LIMITATIONS Paucity of randomized controlled trials, different methods for determining GFR, and substantial heterogeneity. CONCLUSIONS Higher estimated rather than calculated GFR at dialysis therapy initiation is associated with a higher mortality risk in patients with advanced CKD, independent of nutritional status. Although there was substantial heterogeneity of effect size estimates across studies, this observation requires further study.

The changing trends and outcomes in renal replacement therapy: data from the ERA-EDTA Registry

BACKGROUND The mean age of patients starting dialysis increased over the years, as has the proportion of patients with diabetes mellitus, ischaemic heart disease, peripheral vascular disease (PVD), cerebrovascular disease (CD) and malignancy. We assessed dialysis modality choice within subgroups of patients with these comorbidities and in different age categories and subsequently evaluated the association between modality choice and patient survival in these subgroups. METHODS Seven European renal registries participating in the ERA-EDTA Registry provided data from 15,828 incident peritoneal dialysis (PD) and haemodialysis (HD) patients (1998-2006) with available comorbidity data. The likelihood to receive PD rather than HD was assessed with logistic regression and 3-year survival on PD versus HD was evaluated using Cox regression. RESULTS Besides large international variations in the likelihood to receive PD, we found that elderly patients and patients with PVD, CD, malignancy and multiple comorbidities were significantly less likely to receive PD than HD. Overall patients starting on PD had survival benefits [adjusted hazard ratio (HR(adj)) 0.82 (0.75-0.90)], especially patients without comorbidity [HR(adj) 0.65 (0.53-0.80)] or those with malignancy [HR(adj) 0.73 (0.56-0.94)]. In males, survival benefits of PD were independent of diabetic status. Conversely, diabetic females tended to have increased mortality risk on PD [HR(adj) 1.16 (0.93-1.44)], especially if they were >70 years [HR(adj) 1.55 (1.15-2.08)]. CONCLUSIONS In general, modality choice was consistent with expected survival. However, elderly patients, non-diabetic patients and those with malignancy were less likely to receive PD, even though they had decreased mortality risk on PD. Also, although a survival benefit of PD was found for male patients without comorbidity, HD was just as likely to be the chosen dialysis modality as was PD for these patients.