Impact of random variation in albuminuria and estimated glomerular filtration rate on patient enrolment and duration of clinical trials in nephrology.
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ABSTRACT: Aim
To test whether a screening approach with more flexible urinary albumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) thresholds would decrease screen failure rate without negatively impacting on the event rate and overall study duration.Methods
We performed a post-hoc analysis of the ALTITUDE trial. We selected participants randomized to placebo with a UACR of >300 mg/g and an eGFR between 30 mL/min/1.73 m2 and 60 mL/min/1.73 m2 at the first visit (pre-screening) for the trial. We then used less stringent lower UACR and higher eGFR thresholds for the following qualifying visit. For each scenario we calculated the number of eligible participants, the number of renal and cardiovascular endpoints, and the event rates. Based on this, we performed simulations for a future trial and estimated the duration of enrolment and total duration of this trial.Results
The base scenario consisted of 848 participants (median UACR 1239 mg/g; median eGFR 44 mL/min/1.73 m2 ). Lowering the UACR and/or raising eGFR qualification thresholds increased the number of eligible participants, decreased screen failures and resulted in only a modest decrease in renal and cardiovascular event rates. For example, relaxing the UACR criterion from 300 mg/g to 210 mg/g at the qualifying visit, increased the number of eligible patients from 848 to 923, and increased the number of renal events from 117 to 122 events. The event rate showed a moderate decrease from 5.6 (4.6-6.7) events per 100 patient-years to 5.3 (4.4-6.4) events per 100 patient-years. In simulations, lowering the UACR and raising eGFR thresholds for inclusion accelerated patient enrolment and did not increase in the overall trial duration.Conclusion
More flexible albuminuria and eGFR-based inclusion criteria, in participants who met the inclusion criteria of a trial based on pre-screening values prior to the clinical trial, decreases screen failure rates and accelerated patient enrolment leading to more efficient trial conduct without impacting the overall trial duration.
SUBMITTER: Waijer SW
PROVIDER: S-EPMC9306498 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceChronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US.ObjectiveTo evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes.Design, setting, and participantsIndividual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021.ExposuresThe Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR).Main outcomes and measuresThe risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses.ResultsWithin the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]).Conclusions and relevanceIn this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.
| S-EPMC10548311 | biostudies-literature
Project description:It has been suggested that reduced estimated GFR (eGFR) among older adults does not necessarily reflect a pathologic phenomenon.We examined the association between eGFR and albumin-to-creatinine ratio (ACR) and all-cause mortality stratified by age (45 to 59.9, 60 to 69.9, 70 to 79.9, and ?80 years) among 24,350 U.S. adults in the population-based REasons for Geographic and Racial Differences in Stroke (REGARDS) study. A spot urine sample was used to calculate ACR, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to calculate eGFR. All-cause mortality was assessed over a median follow-up of 4.5 years.Among participants ?80 years of age (n = 1669), the age, race, gender, and geographic region of residence adjusted hazard ratios (95% confidence intervals) for mortality associated with eGFR levels of 45 to 59.9 and <45 ml/min per 1.73 m(2), versus ?60 ml/min per 1.73 m(2), were 1.6 (1.3 - 2.1) and 2.2 (1.7 - 2.9), respectively. Also, among participants ?80 years of age, the hazard ratios for mortality associated with ACR levels of 10 to 29.9, 30 to 299.9, and ?300 mg/g, versus <10 mg/g, were 1.7 (1.3 - 2.1), 2.5 (1.9 - 3.3), and 5.1 (3.6 - 7.4), respectively. These associations were present after further multivariable adjustment and within the younger age groupings studied.These data suggest that reduced eGFR and albuminuria confer an increased risk for mortality in all age groups, including adults ?80 years of age.
| S-EPMC3359010 | biostudies-literature
Project description:Rationale & objectiveChronic kidney disease is associated with significant morbidity and mortality in the general population, but little is known about the incidence and risk factors associated with developing low estimated glomerular filtration rate (eGFR) and moderate-severe albuminuria in living kidney donors following nephrectomy.Study designRetrospective, population-based cohort study.Setting & participantsKidney donors in Alberta, Canada.ExposureDonor nephrectomy between May 2001 and December 2017.OutcomeTwo eGFR measurements <45 mL/min/1.73 m2 or 2 measurements of moderate or severe albuminuria from 1-year postdonation onwards that were at least 90 days apart.Analytical approachAssociations between potential risk factors and the primary outcome were assessed using Cox proportional hazard regression analyses.ResultsOver a median follow-up period of 8.6 years (IQR, 4.7-12.6 years), 47 of 590 donors (8.0%) developed sustained low eGFR or moderate-severe albuminuria with an incidence rate of 9.2 per 1,000 person-years (95% confidence interval, 6.6-11.8). The median time for development of this outcome beyond the first year after nephrectomy was 2.9 years (IQR, 1.4-8.0 years). Within the first 4 years of follow-up, a 5 mL/min/1.73 m2 lower predonation eGFR increased the hazard of developing postdonation low eGFR or moderate-severe albuminuria by 26% (adjusted HR, 1.26; 95% CI, 1.10-1.44). Furthermore, donors were at higher risk of developing low eGFR or albuminuria if they had evidence of predonation hypertension (adjusted HR, 2.52; 95% CI, 1.28-4.96) or postdonation diabetes (adjusted HR, 4.72; 95% CI, 1.54-14.50).LimitationsWe lacked data on certain donor characteristics that may affect long-term kidney function, such as race, smoking history, and transplant-related characteristics.ConclusionsA proportion of kidney donors at an incidence rate of 9.2 per 1,000 person-years will develop low eGFR or albuminuria after donation. Donors with lower predonation eGFR, predonation hypertension, and postdonation diabetes are at increased risk of developing this outcome.
| S-EPMC10837092 | biostudies-literature
Project description:ObjectiveTo assess for the presence of a sex interaction in the associations of estimated glomerular filtration rate and albuminuria with all-cause mortality, cardiovascular mortality, and end stage renal disease.DesignRandom effects meta-analysis using pooled individual participant data.Setting46 cohorts from Europe, North and South America, Asia, and Australasia.Participants2,051,158 participants (54% women) from general population cohorts (n=1,861,052), high risk cohorts (n=151,494), and chronic kidney disease cohorts (n=38,612). Eligible cohorts (except chronic kidney disease cohorts) had at least 1000 participants, outcomes of either mortality or end stage renal disease of ≥ 50 events, and baseline measurements of estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (mL/min/1.73 m(2)) and urinary albumin-creatinine ratio (mg/g).ResultsRisks of all-cause mortality and cardiovascular mortality were higher in men at all levels of estimated glomerular filtration rate and albumin-creatinine ratio. While higher risk was associated with lower estimated glomerular filtration rate and higher albumin-creatinine ratio in both sexes, the slope of the risk relationship for all-cause mortality and for cardiovascular mortality were steeper in women than in men. Compared with an estimated glomerular filtration rate of 95, the adjusted hazard ratio for all-cause mortality at estimated glomerular filtration rate 45 was 1.32 (95% CI 1.08 to 1.61) in women and 1.22 (1.00 to 1.48) in men (P(interaction)<0.01). Compared with a urinary albumin-creatinine ratio of 5, the adjusted hazard ratio for all-cause mortality at urinary albumin-creatinine ratio 30 was 1.69 (1.54 to 1.84) in women and 1.43 (1.31 to 1.57) in men (P(interaction)<0.01). Conversely, there was no evidence of a sex difference in associations of estimated glomerular filtration rate and urinary albumin-creatinine ratio with end stage renal disease risk.ConclusionsBoth sexes face increased risk of all-cause mortality, cardiovascular mortality, and end stage renal disease with lower estimated glomerular filtration rates and higher albuminuria. These findings were robust across a large global consortium.
| S-EPMC3558410 | biostudies-literature
Project description:BackgroundClassification of chronic kidney disease (CKD) and evaluation of prognosis is based on two components: estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR). In multiethnic populations, ethnic-specific discrepancies in both parameters may exist. It is unknown whether variations in CKD risk factors may explain these discrepancies.MethodsWe cross-sectionally analyzed baseline eGFR (CKD-EPI formula) and ACR of 21,421 participants (aged 18-70 years) of the HELIUS cohort who were randomly sampled between 2011 and 2015, stratified by ethnicity, through the municipality register of Amsterdam. Six ethnic groups were distinguished, including participants of Dutch (4539), South-Asian Surinamese (3027), African Surinamese (4114), Ghanaian (2297), Turkish (3576) and Moroccan (3868) descent. Multiple regression analyses to determine ethnic differences were performed, with additional adjustments for age, sex, traditional cardiovascular and renal risk factors, and adjustment for level of education.FindingsMean (SE) eGFR was higher in all ethnic minority groups as compared to Dutch participants (eGFR 94.7 ± 0.3 mL/min/1.73 m2) with age- and sex-adjusted differences ranging from 1.5 ± 0.30 in South-Asian Surinamese to 10.1 ± 0.28 mL/min/1.73 m2 in Moroccan participants. ACR was higher in ethnic minority groups as compared to Dutch participants (ACR 0.64 ± 0.20 mg/mmol), with age- and sex-adjusted differences ranging from 0.46 ± 0.20 in African Surinamese participants to 1.70 ± 0.21 mg/mmol in South-Asian Surinamese participants. Differences in both parameters diminished after multiple adjustments, but remained highly significant.InterpretationBoth eGFR and ACR are higher among ethnic minority groups as compared to individuals of Dutch origin-independent of age, sex, prevalence of traditional cardiovascular and renal risk factors, and parameters of socioeconomic status. Future studies should address the potential uncertainty in predicting CKD and CKD-related complications when using both parameters in ethnically diverse populations. Also, identification of driving factors leading to these discrepancies might contribute to improved population screening for CKD.FundingThe HELIUS study is conducted by the Amsterdam University Medical Center and the Public Health Service of Amsterdam. Both organizations provided core support for HELIUS. The HELIUS study is also funded by the Dutch Heart Foundation (2010T084), the Netherlands Organization for Health Research and Development (ZonMw: 200500003), the European Union (FP7: 278901), and the European Fund for the Integration of non-EU immigrants (EIF: 2013EIF013).
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Project description:Background and objectivesExposure to particulate matter (PM) <2.5 μm in aerodynamic diameter (PM2.5) has been linked to detrimental health effects. This study aimed to describe the relationship between long-term PM2.5 exposure and kidney disease, including eGFR, level of albuminuria, and incident CKD.Design, setting, participants, & measurementsThe study included 10,997 participants from the Atherosclerosis Risk in Communities cohort who were followed from 1996-1998 through 2016. Monthly mean PM2.5 concentrations (μg/m3) were estimated at geocoded participant addresses using geographic information system-based, spatiotemporal generalized additive mixed models-including geospatial covariates such as land use-and then averaged over the 12-month period preceding participant examination. Covariate-adjusted, cross-sectional associations of PM2.5, baseline eGFR, and urinary albumin-creatinine ratio (UACR) were estimated using linear regression. PM2.5 and incident CKD (defined as follow-up eGFR <60 ml/min per 1.73 m2 with ≥25% eGFR decline relative to baseline, CKD-related hospitalization or death based on International Classification of Diseases 9/10 codes, or development of ESKD) associations were estimated using Cox proportional hazards regression. Modeling was stratified by study site, and stratum-specific estimates were combined using random-effects meta-analyses.ResultsBaseline mean participant age was 63 (±6) years and eGFR was 86 (±16) ml/min per 1.73 m2. There was no significant PM2.5-eGFR association at baseline. Each 1-μg/m3 higher annual average PM2.5 was associated with higher UACR after adjusting for demographics, socioeconomic status, and clinical covariates (percentage difference, 6.6%; 95% confidence interval [95% CI], 2.6% to 10.7%). Each 1-μg/m3 higher annual average PM2.5 was associated with a significantly higher risk of incident CKD (hazard ratio, 1.05; 95% CI, 1.01 to 1.10).ConclusionsExposure to higher annual average PM2.5 concentrations was associated with a higher level of albuminuria and higher risk for incident CKD in a community-based cohort.
| S-EPMC7057299 | biostudies-literature
Project description:OBJECTIVE:Improved blood pressure control and use of renin-angiotensin-aldosterone system blockers have altered the clinical presentation or phenotype of chronic kidney disease (CKD) in U.S. adults with diabetes. These changes may influence mortality. RESEARCH DESIGN AND METHODS:Data from the National Health and Nutrition Examination Surveys (NHANES) 1988-2006 were used to examine mortality trends in adults with diabetes, defined as physician diagnosis, fasting glucose ≥126 mg/dL, HbA1c >6.5% (48 mmol/mol), or use of glucose-lowering medications. Mortality trends by CKD phenotype (estimated glomerular filtration rate [eGFR] and urine albumin-to-creatinine ratio [ACR] level) were obtained via linkage with the National Death Index through 31 December 2011 while accounting for the complex survey design. RESULTS:From 1988 to 2006, adults with an eGFR <60 mL/min/1.73 m2 and an ACR <30 mg/g increased from ∼0.9 million (95% CI 0.7, 1.1) or 6.6% of the total population with diabetes during years 1988-1994 to 2.4 million (95% CI 1.9, 2.9) or 10.1% of the total population with diabetes during years 2007-2010. Mortality rates generally trended downward for adults with diabetes and an ACR ≥30 mg/g but increased in those with eGFR <60 mL/min/1.73 m2 and an ACR <30 mg/g from 35 deaths per 1,000 person-years (95% CI 22, 55) during years 1988-1994 to 51 deaths per 1,000 person-years (95% CI 33, 83) during years 2003-2006. CONCLUSIONS:ACR values are decreasing in U.S. adults with diabetes, but optimal management strategies are needed to reduce mortality in those with a low eGFR and an ACR <30 mg/g.
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Project description:BackgroundChronic kidney disease (CKD) is associated with an increased cardiovascular disease (CVD) mortality risk. Elevation of cardiac biomarkers in patients with renal dysfunction is ambiguous in the diagnosis of CVD. The purpose of this study was to investigate the associations between estimated glomerular filtration rate (eGFR) and cardiac biomarkers, and the influence of renal dysfunction on the cardiac biomarkers.MethodsWe examined the cross-sectional associations of eGFR with cardiac troponin I (cTnI), creatine kinase (CK), CK-MB, lactic dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), and brain natriuretic peptide (BNP) in 812 adults and 215 child. Spearman correlation and logistic regression analysis were performed to evaluate the associations.ResultsFor adults, lower eGFR CKD-EPI had significantly higher cTnI, CK-MB, LDH, HBDH, and BNP. There were negative correlations between eGFRCKD-EPI and cTnI, CK-MB, LDH, HBDH, and BNP. After adjustment for potential confounders, as compared with eGFRCKD-EPI ≥ 90 mL/min/1.73 m2 , eGFRCKD-EPI < 60 mL/min/1.73 m2 remained associated with a 2.83 (1.08-7.41) [ratio (95% CI)] times higher cTnI and a 6.50 (2.32-18.22) [ratio (95% CI)] times higher HBDH. For child, lower eGFRSchwartz had significant higher CK and CK-MB. There were negative correlations between eGFRSchwartz and CK, and eGFRSchwartz and CK-MB. After adjustment for potential confounders, as compared with eGFRSchwartz ≥ 90 mL/min/1.73 m2 , eGFRSchwartz < 90 mL/min/1.73 m2 revealed no significant higher CVD biomarkers.ConclusionReduced eGFR is associated with elevated cTnI and HBDH among adults without clinically evident CVD, but not child.
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Project description:Clinical predictors for pacemaker-induced cardiomyopathy (PICM) (e.g., a wide QRS duration and left bundle branch block at baseline) have been reported. However, factors involved in the development of PICM in patients with preserved left ventricular ejection fraction (LVEF) remain unknown. This study aimed to determine the risk factors for PICM in patients with preserved LVEF. The data of 113 patients (average age: 71.3 years; men: 54.9%) who had echocardiography before and after pacemaker implantation (PMI) among 465 patients undergoing dual-chamber PMI were retrospectively analyzed. Thirty-three patients were diagnosed with PICM (18.0/100 person-years; 95% CI 12.8-25.2). A univariate Cox regression analysis showed that an estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2 (HR 3.47; 95% CI 1.48-8.16) and a past medical history of coronary artery disease (CAD) (HR 2.76; 95% CI 1.36-5.60) were significantly associated with the onset of PICM. After adjusting for clinical variables, an eGFR ≤ 30 mL/min/1.73 m2 (HR 2.62; 95% CI 1.09-6.29) and a medical history of CAD (HR 2.32; 95% CI 1.13-4.80) were independent risk factors for developing PICM. A medical history of CAD and low eGFR are independent risk factors for PICM in patients with preserved LVEF at baseline. These results could be helpful in predicting a decreased LVEF by ventricular pacing before PMI. Close follow-up by echocardiography is recommended to avoid a delay in upgrading to physiological pacing, such as cardiac resynchronization therapy or conduction system pacing.
| S-EPMC10545821 | biostudies-literature
Project description:BACKGROUND:The usefulness of estimated glomerular filtration rate (eGFR) and albuminuria for prediction of cardiovascular outcomes is controversial. We aimed to assess the addition of creatinine-based eGFR and albuminuria to traditional risk factors for prediction of cardiovascular risk with a meta-analytic approach. METHODS:We meta-analysed individual-level data for 637 315 individuals without a history of cardiovascular disease from 24 cohorts (median follow-up 4·2-19·0 years) included in the Chronic Kidney Disease Prognosis Consortium. We assessed C statistic difference and reclassification improvement for cardiovascular mortality and fatal and non-fatal cases of coronary heart disease, stroke, and heart failure in a 5 year timeframe, contrasting prediction models for traditional risk factors with and without creatinine-based eGFR, albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria), or both. FINDINGS:The addition of eGFR and ACR significantly improved the discrimination of cardiovascular outcomes beyond traditional risk factors in general populations, but the improvement was greater with ACR than with eGFR, and more evident for cardiovascular mortality (C statistic difference 0·0139 [95% CI 0·0105-0·0174] for ACR and 0·0065 [0·0042-0·0088] for eGFR) and heart failure (0·0196 [0·0108-0·0284] and 0·0109 [0·0059-0·0159]) than for coronary disease (0·0048 [0·0029-0·0067] and 0·0036 [0·0019-0·0054]) and stroke (0·0105 [0·0058-0·0151] and 0·0036 [0·0004-0·0069]). Dipstick proteinuria showed smaller improvement than ACR. The discrimination improvement with eGFR or ACR was especially evident in individuals with diabetes or hypertension, but remained significant with ACR for cardiovascular mortality and heart failure in those without either of these disorders. In individuals with chronic kidney disease, the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors; the C statistic for cardiovascular mortality fell by 0·0227 (0·0158-0·0296) after omission of eGFR and ACR compared with less than 0·007 for any single modifiable traditional predictor. INTERPRETATION:Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when these measures are already assessed for clinical purpose or if cardiovascular mortality and heart failure are outcomes of interest. ACR could have particularly broad implications for cardiovascular prediction. In populations with chronic kidney disease, the simultaneous assessment of eGFR and ACR could facilitate improved classification of cardiovascular risk, supporting current guidelines for chronic kidney disease. Our results lend some support to also incorporating eGFR and ACR into assessments of cardiovascular risk in the general population. FUNDING:US National Kidney Foundation, National Institute of Diabetes and Digestive and Kidney Diseases.
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