Ronit Katz

Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.

BACKGROUNDnSubstantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality.nnnMETHODSnIn this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders.nnnFINDINGSnThe analysis included 105,872 participants (730,577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1,128,310 participants (4,732,110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1.73 m(2) and 105 mL/min/1.73 m(2) and increased at lower eGFRs. Compared with eGFR 95 mL/min/1.73 m(2), adjusted HRs for all-cause mortality were 1.18 (95% CI 1.05-1.32) for eGFR 60 mL/min/1.73 m(2), 1.57 (1.39-1.78) for 45 mL/min/1.73 m(2), and 3.14 (2.39-4.13) for 15 mL/min/1.73 m(2). ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0.6 mg/mmol, adjusted HRs for all-cause mortality were 1.20 (1.15-1.26) for ACR 1.1 mg/mmol, 1.63 (1.50-1.77) for 3.4 mg/mmol, and 2.22 (1.97-2.51) for 33.9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements.nnnINTERPRETATIONneGFR less than 60 mL/min/1.73 m(2) and ACR 1.1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease.nnnFUNDINGnKidney Disease: Improving Global Outcomes (KDIGO), US National Kidney Foundation, and Dutch Kidney Foundation.Background nA comprehensive evaluation of the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality is required for assessment of the impact of kidney function on risk in the general population, with implications for improving the definition and staging of chronic kidney disease (CKD).

Mortality and Cardiovascular Risk Across the Ankle-Arm Index Spectrum Results From the Cardiovascular Health Study

Background— A low ankle-arm index (AAI) is a strong predictor of mortality and cardiovascular events. A high AAI also appears to be associated with higher mortality risk in select populations. However, mortality and cardiovascular risk across the AAI spectrum have not been described in a more broadly defined population. Methods and Results— We examined total and cardiovascular mortality and cardiovascular events across the AAI spectrum among 5748 participants in the Cardiovascular Health Study (CHS). The mean age of the sample population was 73±6 years, and the sample included 3289 women (57%) and 883 blacks (15%). The median duration of follow-up was 11.1 (0.1 to 12) years for mortality and 9.6 (0.1 to 12.1) years for cardiovascular events. There were 2311 deaths (953 of which were cardiovascular) and 1491 cardiovascular events during follow-up. After adjustment for potential confounders, AAI measurements ≤0.60 (hazard ratio [HR] 1.82, 95% CI 1.42 to 2.32), 0.61 to 0.7 (HR 2.08, 95% CI 1.61 to 2.69), 0.71 to 0.8 (HR 1.80, 95% CI 1.44 to 2.26), 0.81 to 0.9 (HR 1.73 95% CI 1.43 to 2.11), 0.91 to 1.0 (HR 1.40, 95% CI 1.20 to 1.63), and >1.40 (HR 1.57, 95% CI 1.07 to 2.31) were associated with higher mortality risk from all causes compared with the referent group (AAI 1.11 to 1.20). The pattern was similar for cardiovascular mortality. For cardiovascular events, risk was higher at all AAI levels <1 but not for AAI levels >1.4 (HR 1.00, 95% CI 0.57 to 1.74). The association of a high AAI with mortality was stronger in men than in women and in younger than in older cohort members. Conclusions— In a cohort of community-dwelling elders, mortality risk was higher than the referent category of 1.11 to 1.2 among participants with AAI values above the traditional cutpoint of 0.9 (ie, 0.91 to 1.0 and >1.4), and the specific association of AAI with mortality varied by age and gender.

Vitamin D, Parathyroid Hormone, and Sudden Cardiac Death Results From the Cardiovascular Health Study

Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations, 2 events per 1000 for 25-OHD ≥20 ng/mL and 4 events per 1000 for 25-OHD <20 ng/mL. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations, 2 events per 1000 for PTH <65 pg/mL and 4 events per 1000 for PTH ≥65 pg/mL. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7% of the cohort) had high PTH and low 25-OHD concentrations. This combination was associated with a >2-fold risk of SCD after adjustment (hazard ratio: 2.19 [95% CI: 1.17–4.10]; P=0.017) compared with participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovascular disease.

Association of Arterial Rigidity with Incident Kidney Disease and Kidney Function Decline: The Health ABC Study

BACKGROUND AND OBJECTIVEnThe association of large arterial rigidity and kidney function decline in longitudinal analyses is not well established. This study evaluated the association of aortic pulse wave velocity (aPWV) and pulse pressure (PP) with rapid kidney function decline and incident CKD in the Health, Aging and Body Composition study.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnParticipants were 2129 older adults with a baseline measurement of aPWV, PP, and cystatin C and at least one additional measurement of cystatin C, either at year 3 or year 10. Outcomes were rapid kidney function decline (estimated GFRcysC loss of >3 ml/min per 1.73 m(2) per year) and incident CKD (eGFRcysC < 60 ml/min per 1.73 m(2) in participants with baseline estimated GFR > 60 ml/min per 1.73 m(2)). Multivariate regression models were used to evaluate association of aPWV and PP with each outcome.nnnRESULTSnMean (SD) baseline estimated GFRcysC was 79±29 ml/min per 1.73 m(2). Median follow-up duration was 8.9 years. In multivariable analyses, aPWV was not associated with rapid decline (odds ratio [OR], 95% confidence interval [CI] 1.16, 0.89-1.52) but was associated with incident CKD (incident rate ratio [IRR], 95% CI, 1.39, 1.09-1.77) and PP was associated with both rapid decline (OR, 95% CI 1.10, 1.04-1.16) and incident CKD (IRR, 95% CI, 1.06, 1.01-1.11).nnnCONCLUSIONSnLarge arterial stiffness assessed by aPWV and pulsatility assessed by PP were associated with incident CKD among older adults. Pulsatility assessed by PP was associated with rapid kidney function decline and incident CKD. Future research should determine whether interventions targeting arterial rigidity will prevent CKD development and progression.

Association of a Cystatin C Gene Variant With Cystatin C Levels, CKD, and Risk of Incident Cardiovascular Disease and Mortality

BACKGROUNDnCarriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of chronic kidney disease (CKD), and strengthen risk estimates for cardiovascular disease (CVD) and mortality.nnnSTUDY DESIGNnObservational.nnnSETTING & POPULATIONn4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies.nnnPREDICTORSnWe estimated the association of rs13038305 with eGFRcys and serum creatinine-based eGFR (eGFRcr) and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305.nnnOUTCOMESnWe assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45-59, 60-89, and ≥ 90 mL/min/1.73 m(2). We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis.nnnRESULTSnIn 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%) was associated with a 6.4% lower cystatin C concentration, 5.5-mL/min/1.73 m(2) higher eGFRcys, and 36% [95% CI, 29%-41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14-1.20) and mortality (HR, 1.22; 95% CI, 1.19-1.24) per 10-mL/min/1.73 m(2) lower eGFRcys were similar with or without rs13038305 adjustment. 1,134 (7.7%) participants were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, -0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD.nnnLIMITATIONSnrs13038305 explains only a small proportion of cystatin C variation.nnnCONCLUSIONSnStatistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.