Marlies Noordzij

When do we need competing risks methods for survival analysis in nephrology

Survival analyses are commonly applied to study death or other events of interest. In such analyses, so-called competing risks may form an important problem. A competing risk is an event that either hinders the observation of the event of interest or modifies the chance that this event occurs. For example, when studying death on dialysis, receiving a kidney transplant is an event that competes with the event of interest. Conventional methods for survival analysis ignoring the competing event(s), such as the Kaplan-Meier method and standard Cox proportional hazards regression, may be inappropriate in the presence of competing risks, and alternative methods specifically designed for analysing competing risks data should then be applied. This problem deserves more attention in nephrology research and in the current article, we therefore explain the problem of competing risks in survival analysis and how using different techniques may affect study results.

Sample size calculations: basic principles and common pitfalls

One of the most common requests that statisticians get from investigators are sample size calculations or sample size justifications. The sample size is the number of patients or other experimental units included in a study, and determining the sample size required to answer the research question is one of the first steps in designing a study. Although most statistical textbooks describe techniques for sample size calculation, it is often difficult for investigators to decide which method to use. There are many formulas available which can be applied for different types of data and study designs. However, all of these formulas should be used with caution since they are sensitive to errors, and small differences in selected parameters can lead to large differences in the sample size. In this paper, we discuss the basic principles of sample size calculations, the most common pitfalls and the reporting of these calculations.

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.

Progression of aortic calcification is associated with disorders of mineral metabolism and mortality in chronic dialysis patients

BACKGROUND Previous studies have shown that simple imaging methods may be useful for detection of vascular calcifications in dialysis patients. Based on annual, plain chest X-rays during follow-up on dialysis, we studied the associations of mineral metabolism with the presence and progression of aortic calcification. In addition, we assessed the impact of aortic calcification on mortality. METHODS Three hundred and eighty-four patients who started haemodialysis or peritoneal dialysis between 1997 and 2007 were included (age 61 ± 15 years, 64% male, 61% haemodialysis). Annual chest X-rays were screened for calcification in the aortic arch, and patients were categorized as having no, moderate or severe calcification. Progression was defined as an increase in calcification category during follow-up on dialysis. RESULTS At baseline, 96 (25%) patients had severe, 205 (53%) patients had moderate and 83 (22%) patients had no aortic calcification. For 237 of the 288 patients with no or moderate calcifications at baseline, X-rays were available for follow-up. During follow-up (mean 2.3 years), aortic calcification progressed in 71 patients (30%). We found that baseline plasma calcium > 9.5 mg/dL and iPTH > 300 pg/mL were associated with progression [odds ratios of 3.1, 95% confidence interval (1.2-8.2) and 4.4 (1.4-14.1), respectively]. Progression of aortic calcification was significantly associated with increased risk of all-cause mortality (hazard ratio: 1.9; 95% CI: 1.2-3.1) and cardiovascular mortality (hazard ratio: 2.7; 95% CI: 1.3-5.6). CONCLUSIONS Aortic calcification progressed in almost a third of the patients during dialysis. Hypercalcaemia and hyperparathyroidism were associated with an increased risk of progression. Progression of aortic calcification was significantly related to an increased mortality risk.

Full loss of residual renal function causes higher mortality in dialysis patients; findings from a marginal structural model

BACKGROUND Declining residual renal function, as indicated by the glomerular filtration rate (GFR), is associated with an increased mortality risk in patients with end-stage renal disease (ESRD) on dialysis. METHODS We monitored GFR and mortality in 1800 haemodialysis (HD) and peritoneal dialysis (PD) patients in 1996-2006. We used a marginal structural model to estimate the causal effects both of GFR when it was not completely lost and of the subsequent full loss of GFR on mortality, avoiding the drawbacks of standard regression models that include covariates to adjust for confounding. Instead, effect estimates were adjusted for possible baseline and time-varying confounders using inverse probability weighting. RESULTS We estimated a hazard ratio (HR) corresponding to the effect of the full loss of GFR on mortality, as compared to not having fully lost GFR, of 1.50 [95% confidence interval (CI) 1.09-2.07]. The HR corresponding to the effect of GFR when GFR is not (yet) fully lost on mortality was 0.97 (95% CI 0.92-1.02) (per mL/min/1.73 m(2)). We found no significant difference in the effect of GFR on mortality between patients starting on PD and HD. CONCLUSIONS Preventing or delaying the full loss of GFR can improve survival in dialysis patients. This supports the importance that is given to the effect of treatment options for patients with ESRD on the rate of decline of the residual renal function.

Sample size calculations.

The sample size is the number of patients or other experimental units that need to be included in a study to answer the research question. Pre-study calculation of the sample size is important; if a sample size is too small, one will not be able to detect an effect, while a sample that is too large may be a waste of time and money. Methods to calculate the sample size are explained in statistical textbooks, but because there are many different formulas available, it can be difficult for investigators to decide which method to use. Moreover, these calculations are prone to errors, because small changes in the selected parameters can lead to large differences in the sample size. This paper explains the basic principles of sample size calculations and demonstrates how to perform such a calculation for a simple study design.

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

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.

A positive effect of AII inhibitors on peritoneal membrane function in long-term PD patients

BACKGROUND Experimental studies showed that inhibition of AII effects attenuates the development of peritoneal membrane fibrosis and neoangiogenesis. The latter leads to an increase of peritoneal solute transport and ultrafiltration failure. The results of a single-centre study showed that use of ACEI/ARB can prevent the increase of small solute transport in long-term PD patients. Our aim was to investigate whether these results would also be present in a larger population and influence patient and technique survival in long-term PD. METHODS We analysed data from 217 long-term CAPD patients, participating in the Netherlands Cooperative Study on Adequacy of Dialysis (NECOSAD). Included patients underwent CAPD therapy for at least 2 years; 120 of them were treated with the ACE/AII inhibitors-ACEI/ARB group. The control group consisted of 87 patients who received none of the above drugs and 10 patients who had them for <25% of their time on PD. RESULTS A significant difference in the time course of peritoneal transport was found between the two groups. The value of 24-h D/P creatinine was associated with the PD duration (P = 0.01) and its time course was influenced by use of ACEI/ARB (P = 0.05). We found no effect of ACEI/ARB on patient survival, but some benefit was found for the technique survival: in a multivariate model the hazard ratio for the group with the longest use of ACEI/ARB was 0.5 (CI 0.22-1.4), P = 0.19. CONCLUSIONS We conclude that AII inhibition prevents the increase in small solute transport in long-term PD. These drugs may also have some positive influence on PD technique survival.

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

BACKGROUND This study examines the time trends in incidence, prevalence, patient and kidney allograft survival and causes of death (COD) in patients receiving renal replacement therapy (RRT) in Europe. METHODS Eighteen national or regional renal registries providing data to the European Renal Association-European Dialysis and Transplant Association Registry between 1998 and 2011 were included. Incidence and prevalence time trends between 2001 and 2011 were studied with Joinpoint and Poisson regression. Patient and kidney allograft survival and COD between 1998 and 2011 were analysed using Kaplan-Meier and competing risk methods and Cox regression. RESULTS From 2001 to 2008, the adjusted incidence of RRT rose by 1.1% (95% CI: 0.6, 1.7) annually to 131 per million population (pmp). During 2008-2011, the adjusted incidence fell by 2.2% (95% CI: -4.2, -0.2) annually to 125 pmp. This decline occurred predominantly in patients aged 45-64 years, 65-74 years and in the primary renal diseases diabetes mellitus type 1 and 2, renovascular disease and glomerulonephritis. Between 2001 and 2011, the overall adjusted prevalence increased from 724 to 1032 pmp (+3.3% annually, 95% CI: 2.8, 3.8). The adjusted 5-year patient survival on RRT improved between 1998-2002 and 2003-2007 [adjusted hazard ratio (HRa) 0.85, 95% CI: 0.84, 0.86]. Comparing these time periods, the risk of cardiovascular deaths fell by 25% (HRa 0.75, 95% CI: 0.74, 0.77). However the risk of malignant death rose by 9% (HRa 1.09, 95% CI: 1.03, 1.16) in patients ≥65 years. CONCLUSION This European study shows a declining RRT incidence, particularly in patients aged 45-64 years, 65-74 years and secondary to diabetic nephropathy. Encouragingly, the adjusted RRT patient survival continues to improve. The risk of cardiovascular death has decreased, though the risk of death from malignancy has increased in the older population.

Factors Influencing the Decision to Start Renal Replacement Therapy: Results of a Survey Among European Nephrologists

BACKGROUND Little is known about the criteria nephrologists use in the decision of when to start renal replacement therapy (RRT) in early referred adult patients. We evaluated opinions of European nephrologists on the decision for when to start RRT. STUDY DESIGN European web-based survey. PREDICTORS Patient presentations described as uncomplicated patients, patients with unfavorable clinical and unfavorable social conditions, or patients with specific clinical, social, and logistical factors. SETTING & PARTICIPANTS Nephrologists from 11 European countries. OUTCOMES & MEASUREMENTS We studied opinions of European nephrologists about the influence of clinical, social, and logistical factors on decision making regarding when to start RRT, reflecting practices in place in 2009. Questions included target levels of kidney function at the start of RRT and factors accelerating or postponing RRT initiation. Using linear regression, we studied determinants of target estimated glomerular filtration rate (eGFR) at the start of RRT. RESULTS We received 433 completed surveys. The median target eGFR selected to start RRT in uncomplicated patients was 10.0 (25th-75th percentile, 8.0-10.0) mL/min/1.73 m(2). Level of excretory kidney function was considered the most important factor in decision making regarding uncomplicated patients (selected by 54% of respondents); in patients with unfavorable clinical versus social conditions, this factor was selected by 24% versus 32%, respectively. Acute clinical factors such as life-threatening hyperkalemia refractory to medical therapy (100%) and uremic pericarditis (98%) elicited a preference for an immediate start, whereas patient preference (69%) and vascular dementia (66%) postponed the start. Higher target eGFRs were reported by respondents from high- versus low-RRT-incidence countries (10.4 [95% CI, 9.9-10.9] vs 9.1 mL/min/1.73 m(2)) and from for-profit versus not-for-profit centers (10.1 [95% CI, 9.5-10.7] vs 9.5 mL/min/1.73 m(2)). LIMITATIONS We were unable to calculate the exact response rate and examined opinions rather than practice for 433 nephrologists. CONCLUSIONS Only for uncomplicated patients did half the nephrologists consider excretory kidney function as the most important factor. Future studies should assess the weight of each factor affecting decision making.