Importance The established chronic kidney disease (CKD) progression endpoint, end-stage renal disease (ESRD) or doubling of serum creatinine (corresponding to a change in estimated glomerular filtration rate (eGFR) of −57% or greater) is a late event, limiting feasibility of nephrology clinical trials. Objective To characterize the association of decline in eGFR with subsequent progression to ESRD, with implications for using lesser declines in eGFR as potential alternative endpoints for CKD progression. Since most people with CKD die before reaching ESRD, we also investigated mortality risk. Data Sources Individual meta-analysis of up to 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts. Study Selection Cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine over 1-3 years and outcome data. Data Extraction and Synthesis Transfer of individual participant data or standardized analysis of outputs for random effects meta-analysis took place between July 2012 and September 2013 with baseline eGFRs during 1975-2012. Main Outcomes and Measures ESRD (initiation of dialysis or transplantation) or all-cause mortality risk related to percent change in eGFR over 2 years adjusted for potential confounders and first eGFR. Results The adjusted hazard ratios (HR) of ESRD and mortality were exponentially higher with larger eGFR decline. Among participants with baseline eGFR <60 ml/min/1.73m2, the adjusted HRs for ESRD were 32.1 (95% CI 22.3-46.3) and 5.4 (4.5-6.4) for −57% and −30% eGFR changes, respectively. However, changes of −30% or greater were much more common than changes of −57% (6.9% (6.4-7.4%) vs. 0.79% (0.52-1.06%) in the whole consortium). This association was strong and consistent across length of baseline (1 or 3 years), baseline eGFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD for eGFR changes of −57%, −40%, −30% and 0% were 99% (95-100%), 83% (71-93%), 64% (52-77%), vs. 18% (15-22%) respectively at baseline eGFR of 35 ml/min/1.73m2. Corresponding mortality risks were 77% (71-82%), 60% (56-63%), 50% (47-52%), vs. 32% (31-33%), showing a similar but weaker pattern. Conclusions and Relevance Declines in eGFR smaller than doubling of serum creatinine occur more commonly and are strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in eGFR, such as 30% reduction over 2 years, as an alternative endpoint for CKD progression.

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Limited data are available on the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end stage renal disease (ESRD) among individuals with chronic kidney disease (CKD). We conducted a collaborative meta-analysis of 21,688 participants selected for CKD from 13 cohorts. After adjustment for potential confounders and albuminuria, a 15 mL/min/1.73 m2 lower eGFR below 45 mL/min/1.73 m2 was significantly associated with mortality (pooled hazard ratio [HR] 1.47 [95% CI: 1.22–1.79]), and ESRD (pooled HR 6.24 [95% CI: 4.84–8.05]). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eight-fold higher albumin:creatinine ratio (ACR) or protein:creatinine ratio (PCR) was significantly associated with mortality (pooled HR 1.40 [95% CI: 1.27–1.55]), without evidence of significant heterogeneity. An eight-fold higher ACR or PCR was also strongly associated with ESRD (pooled HR 3.04 [95% CI: 2.27–4.08]), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD. The associations are stronger for ESRD than for mortality. The observed associations are consistent with CKD classification based on eGFR stages, and suggest that albuminuria provides additional prognostic information among individuals with CKD.

Current literature suggests associations between abnormal mineral metabolism (MM) to cardiovascular disease in dialysis populations, with conflicting results. MM physiology is complex; therefore, it was hypothesized that constellations of MM parameters, reflecting this complexity, would be predictive of mortality and that this effect would be modified by dialysis duration (DD). Prevalent dialysis patients in British Columbia, Canada, who had measurements of calcium (Ca), phosphate (Pi), and parathyroid hormone (iPTH) between January and March 2000 were followed prospectively until December 2002. Statistical analysis included Cox proportional hazard models with Ca, Pi, and iPTH alone and in combination as explanatory variables; analyses were stratified by DD. The 515 patients included in this analysis represent British Columbia and Canadian dialysis populations: 69% were on hemodialysis, mean age was 60 +/- 17 yr, 40% were female, and 34% had diabetes. Mean Ca and Pi values were 2.32 +/- 0.22 mmol/L and 1.68 +/- 0.59 mmol/L, respectively, and median iPTH was 15.8 pmol/L (25th to 75th percentile: 6.9 to 37.3 pmol/L). Serum Pi, after adjusting for demographic, dialysis type and adequacy, hemoglobin, and albumin, independently predicted mortality (risk ratio [RR], 1.56 per 1 mmol/L; 95% confidence interval [CI], 1.15 to 2.12; P = 0.004). When combinations of parameters were modeled (overall P = 0.003), the combinations of high serum Pi and Ca with high iPTH (RR, 3.71; 95% CI, 1.53 to 9.03; P = 0.004) and low iPTH (RR, 4.30; 95% CI, 2.01 to 9.22; P < 0.001) had highest risks for mortality as compared with the combination of high iPTH with normal serum Ca and Pi that had the lowest mortality and was used as index category. These effects varied across different strata of DD. This analysis demonstrates the importance of examining combinations of MM parameters as opposed to single variables alone and the effect of DD. In so doing, the complex interaction of time and MM can begin to be understand. Further exploration is required.

Objective To 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.Design Random effects meta-analysis using pooled individual participant data.Setting 46 cohorts from Europe, North and South America, Asia, and Australasia.Participants 2 051 158 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 RESEARCHof 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.Conclusions Both 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. IntroductionChronic kidney disease affects 10-16% of the general adult population in Asia, Europe, Australia, and the United States. [1][2][3][4][5][6] Chronic kidney disease, typically defined by reduced estimated glomerular filtration rate and/or albuminuria, is independently associated with an increased risk of all-cause mortality and cardiovascular mortality and progression to end stage renal disease. [7][8][9] Go and colleagues found in administrative healthcare data that estimated glomerular filtration rates <60 mL/min/1.73m2 were independently associated with hospitalisations, cardiovascular events, and death. 10 In a collaborative meta-analysis of general population cohorts we found that mortality rises exponentially with decreasing estimated glomerular filtration rate below 60 mL...

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