Informative censoring in transplantation statistics

Observations are informatively censored when there is dependence between the time to the event of interest and time to censoring. When considering the time to death of patients on the waiting list for a transplant, particularly a liver transplant, patients that are removed for transplantation are potentially informatively censored, as generally the most ill patients are transplanted. If this censoring is assumed to be non-informative then any inferences may be misleading.The existing methods in the literature that account for informative censoring are applied to data to assess their suitability for the liver transplantation setting. As the amount of dependence between the time to failure and time to censoring variables cannot be identified from the observed data, estimators that give bounds on the marginal survival function for a given range of dependence values are considered. However, the bounds are too wide to be of use in practice. Sensitivity analyses are also reviewed as these allow us to assess how inferences are affected by assuming differing amounts of dependence and whether methods that account for informative censoring are necessary. Of the other methods considered IPCW estimators were found to be the most useful in practice.Sensitivity analyses for parametric models are less computationally intensive than those for Cox models, although they are not suitable for all sets of data. Therefore, we develop a sensitivity analysis for piecewise exponential models that is still quick to apply. These models are flexible enough to be suitable for a wide range of baseline hazards. The sensitivity analysis suggests that for the liver transplantation setting the inferences about time to failure are sensitive to informative censoring. A simulation study is carried out that shows that the sensitivity analysis is accurate in many situations, although not when there is a large proportion of censoring in the data set. Finally, a method to calculate the survival benefit of liver transplantation is adapted to make it more suitable for UK data. This method calculates the expected change in post-transplant mortality relative to waiting list mortality. It uses IPCW methods to account for the informative censoring encountered when estimating waiting list mortality to ensure the estimated survival benefit is as accurate as possible

The impact of social disadvantage in moderate-to-severe chronic kidney disease: an equity-focused systematic review

It is unclear whether a social gradient in health outcomes exists for people with moderate-to-severe chronic kidney disease (CKD). We critically review the literature for evidence of social gradients in health and investigate the ‘suitability’ of statistical analyses in the primary studies. In this equity-focused systematic review among adults with moderate-to-severe CKD, factors of disadvantage included gender, race/ethnicity, religion, education, socio-economic status or social capital, occupation and place of residence. Outcomes included access to healthcare, kidney disease progression, cardiovascular events, allcause mortality and suitability of analyses. Twenty-four studies in the pre-dialysis population and 34 in the dialysis population representing 8.9 million people from 10 countries were included. In methodologically suitable studies among pre-dialysis patients, a significant social gradient was observed in access to healthcare for those with no health insurance and no home ownership. Low income and no home ownership were associated with higher cardiovascular event rates and higher mortality [HR 1.94, 95% confidence interval (CI) 1.27–2.98; HR 1.28, 95% CI 1.04–1.58], respectively. In methodologically suitable studies among dialysis patients, females, ethnic minorities, those with low education, no health insurance, low occupational level or no home ownership were significantly less likely to access cardiovascular healthcare than their more advantaged dialysis counterparts. Low education level and geographic remoteness were associated with higher cardiovascular event rates and higher mortality (HR 1.54, 95% CI 1.01–2.35; HR 1.21, 95% CI 1.08–1.37), respectively. Socially disadvantaged pre-dialysis and dialysis patients experience poorer access to specialist cardiovascular health services, and higher rates of cardiovascular events and mortality than their more advantaged counterparts

Conventional and Genetic Evidence on the Association between Adiposity and CKD

Background The size of any causal contribution of central and general adiposity to CKD risk and the underlying mechanism of mediation are unknown. Methods Data from 281,228 UK Biobank participants were used to estimate the relevance of waist-to-hip ratio and body mass index (BMI) to CKD prevalence. Conventional approaches used logistic regression. Genetic analyses used Mendelian randomization (MR) and data from 394 waist-to-hip ratio and 773 BMI-associated loci. Models assessed the role of known mediators (diabetes mellitus and BP) by adjusting for measured values (conventional analyses) or genetic associations of the selected loci (multivariable MR). Results Evidence of CKD was found in 18,034 (6.4%) participants. Each 0.06 higher measured waist-to-hip ratio and each 5-kg/m2 increase in BMI were associated with 69% (odds ratio, 1.69; 95% CI, 1.64 to 1.74) and 58% (1.58; 1.55 to 1.62) higher odds of CKD, respectively. In analogous MR analyses, each 0.06–genetically-predicted higher waist-to-hip ratio was associated with a 29% (1.29; 1.20 to 1.38) increased odds of CKD, and each 5-kg/m2 genetically-predicted higher BMI was associated with a 49% (1.49; 1.39 to 1.59) increased odds. After adjusting for diabetes and measured BP, chi-squared values for associations for waist-to-hip ratio and BMI fell by 56%. In contrast, mediator adjustment using multivariable MR found 83% and 69% reductions in chi-squared values for genetically-predicted waist-to-hip ratio and BMI models, respectively. Conclusions Genetic analyses suggest that conventional associations between central and general adiposity with CKD are largely causal. However, conventional approaches underestimate mediating roles of diabetes, BP, and their correlates. Genetic approaches suggest these mediators explain most of adiposity-CKD–associated risk.</p

Relationship between clinic and ambulatory blood pressure and mortality: an observational cohort study in 59 124 patients

BACKGROUND: Ambulatory blood pressure provides a more comprehensive assessment than clinic blood pressure, and has been reported to better predict health outcomes than clinic or home pressure. We aimed to examine associations of clinic and 24-h ambulatory blood pressure with all-cause and cardiovascular mortality in a large cohort of primary care patients referred for assessment of hypertension. METHODS: We did an observational cohort study using clinic and ambulatory blood pressure data obtained from March 1, 2004, to Dec 31, 2014, from the Spanish Ambulatory Blood Pressure Registry. This registry included patients from 223 primary care centres from the Spanish National Health System in all 17 regions of Spain. Mortality data (date and cause) were ascertained by a computerised search of the vital registry of the Spanish National Institute of Statistics. Complete data were available for age, sex, all blood pressure measures, and BMI. For each study participant, follow-up was from the date of their recruitment to the date of death or Dec 31, 2019, whichever occurred first. Cox models were used to estimate associations between usual clinic or ambulatory blood pressure and mortality, adjusted for confounders and additionally for alternative measures of blood pressure. For each measure of blood pressure, we created five groups (ie, fifths) defined by quintiles of that measure among those who subsequently died. FINDINGS: During a median follow-up of 9·7 years, 7174 (12·1%) of 59 124 patients died, including 2361 (4·0%) from cardiovascular causes. J-shaped associations were observed for several blood pressure measures. Among the top four baseline-defined fifths, 24-h systolic blood pressure was more strongly associated with all-cause death (hazard ratio [HR] 1·41 per 1 - SD increment [95% CI 1·36-1·47]) than clinic systolic blood pressure (1·18 [1·13-1·23]). After adjustment for clinic blood pressure, 24-h blood pressure remained strongly associated with all-cause deaths (HR 1·43 [95% CI 1·37-1·49]), but the association between clinic blood pressure and all-cause death was attenuated when adjusted for 24-h blood pressure (1·04 [1·00-1·09]). Compared with the informativeness of clinic systolic blood pressure (100%), night-time systolic blood pressure was most informative about risk of all-cause death (591%) and cardiovascular death (604%). Relative to blood pressure within the normal range, elevated all-cause mortality risks were observed for masked hypertension (HR 1·24 [95% CI 1·12-1·37]) and sustained hypertension (1·24 [1·15-1·32]), but not white-coat hypertension, and elevated cardiovascular mortality risks were observed for masked hypertension (1·37 [1·15-1·63]) and sustained hypertension (1·38 [1·22-1·55]), but not white-coat hypertension. INTERPRETATION: Ambulatory blood pressure, particularly night-time blood pressure, was more informative about the risk of all-cause death and cardiovascular death than clinic blood pressure. FUNDING: Spanish Society of Hypertension, Lacer Laboratories, UK Medical Research Council, Health Data Research UK, National Institute for Health and Care Research Biomedical Research Centres (Oxford and University College London Hospitals), and British Heart Foundation Centre for Research Excellence

Frailty, multimorbidity and polypharmacy: exploratory analyses of the effects of empagliflozin from the EMPA-KIDNEY trial

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recommended treatment for adults with chronic kidney disease (CKD), but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin’s risk-benefit profile in a post-hoc analysis of the double-blind, placebocontrolled EMPA-KIDNEY trial. Methods: The EMPA-KIDNEY trial randomized 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20<45 mL/min/1.73m2 , or ≥45<90 mL/min/1.73m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed for two years (median). Additional characteristics analysed in subgroups were multimorbidity, polypharmacy and health-related quality of life (HRQoL) at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. Results: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility and diabetes; then eGFR and other comorbidities. Empagliflozin was generally well-tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.64-0.82); and all-cause hospitalization by 14% (HR 0.86, 95% CI 0.78-0.95); with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy or HRQoL. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. Conclusions: These findings support the use of SGLT2 inhibitors in CKD, irrespective of frailty, multimorbidity or polypharmacy

Effects of empagliflozin on fluid overload, weight and blood pressure in chronic kidney disease

BACKGROUND: Chronic kidney disease (CKD) is associated with fluid excess which can be estimated by bioimpedance spectroscopy. We aimed to assess effects of sodium glucose co-transporter 2 inhibition on bioimpedance-derived “Fluid Overload” and adiposity in a CKD population. METHODS: EMPA-KIDNEY was a 6609-participant double-blind placebo-controlled trial of empagliflozin 10 mg once daily in patients with CKD at risk of progression. In a 660-participant substudy, bioimpedance measurements were added to the main trial procedures at randomization, 2- and 18-month follow-up visits. The substudy’s primary outcome was the study-average difference in absolute “Fluid Overload” (an estimate of excess extracellular water) analyzed using a mixed-model repeated measures approach. RESULTS: The 660 substudy participants were broadly representative of the 6609- participant trial population. Substudy mean baseline absolute “Fluid Overload” was 0.4±1.7 L. Compared to placebo, the overall mean absolute “Fluid Overload” difference among those allocated empagliflozin was -0.24 L (95%CI -0.38, -0.11), with similar-sized differences at 2- and 18-months, and in pre-specified subgroups. Total body water differences comprised between-group differences in extracellular water of -0.49 L (95%CI -0.69, -0.30, including the -0.24 L “Fluid Overload” difference); and a -0.30 L (95%CI -0.57, -0.03) difference in intracellular water. There was no significant effect of empagliflozin on bioimpedance-derived adipose tissue mass (- 0.28 [95%CI -1.41, 0.85] kg). The between-group difference in weight was -0.7 kg (95%CI -1.3, -0.1). CONCLUSIONS: In a broad range of patients with CKD, empagliflozin resulted in a sustained reduction in a bioimpedance-derived estimate of fluid overload, with no statistically significant effect on fat mass

Impact of Educational Attainment on Health Outcomes in Moderate to Severe CKD

BackgroundThe inverse association between educational attainment and mortality is well established, but its relevance to vascular events and renal progression in a population with chronic kidney disease (CKD) is less clear. This study aims to determine the association between highest educational attainment and risk of vascular events, cause-specific mortality, and CKD progression.Study DesignProspective epidemiologic analysis among participants in the Study of Heart and Renal Protection (SHARP), a randomized controlled trial.Setting & Participants9,270 adults with moderate to severe CKD (6,245 not receiving dialysis at baseline) and no history of myocardial infarction or coronary revascularization recruited in Europe, North America, Asia, Australia, and New Zealand.PredictorHighest educational attainment measured at study entry using 6 levels that ranged from “no formal education” to “tertiary education.”OutcomesAny vascular event (any fatal or nonfatal cardiac, cerebrovascular, or peripheral vascular event), cause-specific mortality, and CKD progression during 4.9 years’ median follow-up.ResultsThere was a significant trend (P<0.001) toward increased vascular risk with decreasing levels of education. Participants with no formal education were at a 46% higher risk of vascular events (relative risk [RR], 1.46; 95% CI, 1.14-1.86) compared with participants with tertiary education. The trend for mortality across education levels was also significant (P<0.001): all-cause mortality was twice as high among those with no formal education compared with tertiary-educated individuals (RR, 2.05; 95% CI, 1.62-2.58), and significant increases were seen for both vascular (RR, 1.84; 95% CI, 1.21-2.81) and nonvascular (RR, 2.15; 95% CI, 1.60-2.89) deaths. Lifestyle factors and prior disease explain most of the excess mortality risk. Among 6,245 participants not receiving dialysis at baseline, education level was not significantly associated with progression to end-stage renal disease or doubling of creatinine level (P for trend = 0.4).LimitationsNo data for employment or health insurance coverage.ConclusionsLower educational attainment is associated with increased risk of adverse health outcomes in individuals with CKD

Impact of CKD on Household Income

Introduction The impact of chronic kidney disease (CKD) on income is unclear. We sought to determine whether CKD severity, serious adverse events, and CKD progression affected household income. Methods Analyses were undertaken in a prospective cohort of adults with moderate-to-severe CKD in the Study of Heart and Renal Protection (SHARP), with household income information available at baseline screening and study end. Logistic regressions, adjusted for sociodemographic characteristics, smoking, and prior diseases at baseline, estimated associations during the 5-year follow-up, among (i) baseline CKD severity, (ii) incident nonfatal serious adverse events (vascular or cancer), and (iii) CKD treatment modality (predialysis, dialysis, or transplanted) at study end and the outcome “fall into relative poverty.” This was defined as household income <50% of country median income. Results A total of 2914 SHARP participants from 14 countries were included in the main analysis. Of these, 933 (32%) were in relative poverty at screening; of the remaining 1981, 436 (22%) fell into relative poverty by study end. Compared with participants with stage 3 CKD at baseline, the odds of falling into poverty were 51% higher for those with stage 4 (odds ratio [OR]: 1.51; 95% confidence interval [CI]: 1.09–2.10), 66% higher for those with stage 5 (OR: 1.66; 95% CI: 1.11–2.47), and 78% higher for those on dialysis at baseline (OR: 1.78, 95% CI: 1.22–2.60). Participants with kidney transplant at study end had approximately half the risk of those on dialysis or those with CKD stages 3 to 5. Conclusion More advanced CKD is associated with increased odds of falling into poverty. Kidney transplantation may have a role in reducing this risk

Empagliflozin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background Empagliflozin has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory, metabolic, and haemodynamic effects. The RECOVERY trial aimed to assess its safety and efficacy in patients admitted to hospital with COVID-19. Methods In the randomised, controlled, open-label RECOVERY trial, several possible treatments are compared with usual care in patients hospitalised with COVID-19. In this analysis, we assess eligible and consenting adults who were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus oral empagliflozin 10 mg once daily for 28 days or until discharge (whichever came first) using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality; secondary outcomes were duration of hospitalisation and (among participants not on invasive mechanical ventilation at baseline) the composite of invasive mechanical ventilation or death. On March 3, 2023 the independent data monitoring committee recommended that the investigators review the data and recruitment was consequently stopped on March 7, 2023. The ongoing RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings Between July 28, 2021 and March 6, 2023, 4271 patients were randomly allocated to receive either empagliflozin (2113 patients) or usual care alone (2158 patients). Primary and secondary outcome data were known for greater than 99% of randomly assigned patients. Overall, 289 (14%) of 2113 patients allocated to empagliflozin and 307 (14%) of 2158 patients allocated to usual care died within 28 days (rate ratio 0·96 [95% CI 0·82–1·13]; p=0·64). There was no evidence of significant differences in duration of hospitalisation (median 8 days for both groups) or the proportion of patients discharged from hospital alive within 28 days (1678 [79%] in the empagliflozin group vs 1677 [78%] in the usual care group; rate ratio 1·03 [95% CI 0·96–1·10]; p=0·44). Among those not on invasive mechanical ventilation at baseline, there was no evidence of a significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (338 [16%] of 2084 vs 371 [17%] of 2143; risk ratio 0·95 [95% CI 0·84–1·08]; p=0·44). Two serious adverse events believed to be related to empagliflozin were reported: both were ketosis without acidosis. Interpretation In adults hospitalised with COVID-19, empagliflozin was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death so is not indicated for the treatment of such patients unless there is an established indication due to a different condition such as diabetes. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research (MC_PC_19056), and Wellcome Trust (222406/Z/20/Z)