Slope of Kidney Function and Its Association with Longitudinal Mortality and Cardiovascular Disease among Individuals with CKD.

BACKGROUND: Slopes of eGFR have been associated with increased risks of death and cardiovascular events in a U-shaped fashion. Poor outcomes in individuals with rising eGFR are potentially attributable to sarcopenia, hemodilution, and other indicators of clinical deterioration. METHODS: To investigate the association between eGFR slopes and risks of death or cardiovascular events, accounting for multiple confounders, we studied 2738 individuals with moderate to severe CKD participating in the multicenter Chronic Renal Insufficiency Cohort (CRIC) Study. We used linear, mixed-effects models to estimate slopes with up to four annual eGFR assessments, and Cox proportional hazards models to investigate the association between slopes and the risks of death and cardiovascular events. RESULTS: Slopes of eGFR had a bell-shaped distribution (mean [SD], -1.5 [-2] ml/min per 1.73 m2 per year). Declines of eGFR that were steeper than the average decline associated with progressively increasing risks of death (hazard ratio [HR], 1.23; 95% confidence interval [95% CI], 1.09 to 1.39; for a slope 1 SD below the average) and cardiovascular events (HR, 1.19; 95% CI, 1.03 to 1.38). Rises of eGFR or declines lower than the average decline were not associated with the risk of death or cardiovascular events. CONCLUSIONS: In a cohort of individuals with moderate to severe CKD, we observed steep declines of eGFR were associated with progressively increasing risks of death and cardiovascular events; however, we found no increased risks associated with eGFR improvement. These findings support the potential value of eGFR slopes in clinical assessment of adults with CKD.

A collaborative, individual-level analysis compared longitudinal outcomes across the International Network of Chronic Kidney Disease (iNETCKD) cohorts.

Rates of chronic kidney disease (CKD) progression, end stage kidney disease (ESKD), all-cause mortality, and cardiovascular (CVD) events among individuals with CKD vary widely across countries. Well-characterized demographic, comorbidity, and laboratory markers captured for prospective cohorts may explain, in part, such differences. To investigate whether core characteristics of individuals with CKD explain differences in rates of outcomes, we conducted an individual-level analysis of eight studies that are part of iNET-CKD, an international network of CKD cohort studies. Overall, the rate of CKD progression was 40 events/1000 person-year (95% confidence interval 39 - 41), 28 (27 - 29) for ESKD, 41 (40 - 42) for death, and 29 (28 - 30) for CVD events. However, standardized rates were highly heterogeneous across studies (over 92.5%). Interactions by study group on the association between baseline characteristics and outcomes were then identified. For example, the adjusted hazard ratio for CKD progression was 0.44 (95% confidence interval 0.35 - 0.56) for women vs. men among the Japanese (CKD-JAC), while it was 0.66 (0.59 - 0.75) among the Uruguayan (NRHP). The adjusted hazard ratio for ESKD was 2.02 (95% CI 1.88 - 2.17) per 10 units lower baseline eGFR among Americans (CRIC), while it was 3.01 (2.57 - 3.53) among Canadians (CanPREDDICT) (significant interaction for comparisons across all studies). The risks of CKD progression, ESKD, death, and CVD vary across countries even after accounting for the distributions of age, sex, comorbidities, and laboratory markers. Thus, our findings support the need for a better understanding of specific factors in different populations that explain this variation.

Hematuria as a risk factor for progression of chronic kidney disease and death: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Hematuria is associated with chronic kidney disease (CKD), but has rarely been examined as a risk factor for CKD progression. We explored whether individuals with hematuria had worse outcomes compared to those without hematuria in the CRIC Study. METHODS: Participants were a racially and ethnically diverse group of adults (21 to 74 years), with moderate CKD. Presence of hematuria (positive dipstick) from a single urine sample was the primary predictor. Outcomes included a 50% or greater reduction in eGFR from baseline, ESRD, and death, over a median follow-up of 7.3 years, analyzed using Cox Proportional Hazards models. Net reclassification indices (NRI) and C statistics were calculated to evaluate their predictive performance. RESULTS: Hematuria was observed in 1145 (29%) of a total of 3272 participants at baseline. Individuals with hematuria were more likely to be Hispanic (22% vs. 9.5%, respectively), have diabetes (56% vs. 48%), lower mean eGFR (40.2 vs. 45.3 ml/min/1.73 m2), and higher levels of urinary albumin > 1.0 g/day (36% vs. 10%). In multivariable-adjusted analysis, individuals with hematuria had a greater risk for all outcomes during the first 2 years of follow-up: Halving of eGFR or ESRD (HR Year 1: 1.68, Year 2: 1.36), ESRD (Year 1: 1.71, Year 2: 1.39) and death (Year 1:1.92, Year 2: 1.77), and these associations were attenuated, thereafter. Based on NRIs and C-statistics, no clear improvement in the ability to improve prediction of study outcomes was observed when hematuria was included in multivariable models. CONCLUSION: In a large adult cohort with CKD, hematuria was associated with a significantly higher risk of CKD progression and death in the first 2 years of follow-up but did not improve risk prediction.

Matrix Metalloproteinase-2 and CKD Progression: The Chronic Renal Insufficiency Cohort (CRIC) Study.

Rationale & Objective: Matrix metalloproteinase 2 (MMP-2) plays an important role in the development of fibrosis, the final common pathway of chronic kidney disease (CKD). This study aimed to assess the relationship between repeated measures of MMP-2 and CKD progression in a large, diverse prospective cohort. Study Design: In a prospective cohort of Chronic Renal Insufficiency Cohort (CRIC) participants (N = 3,827), MMP-2 was measured at baseline. In a case-cohort design, MMP-2 was additionally measured at year 2 in a randomly selected subcohort and cases of estimated glomerular filtration rate (eGFR) halving or kidney replacement therapy (KRT) (N = 1,439). Setting & Participants: CRIC is a multicenter prospective cohort of adults with CKD. Exposure: MMP-2 measured in plasma at baseline and at year 2. Outcomes: A composite kidney endpoint (KRT/eGFR halving). Analytical Approach: Weighted Cox proportional hazards models for case-cohort participants. Results: Participants were followed for a median of 4.6 years from year 2 and 6.9 years from the baseline. Persistently elevated MMP-2 (≥300 ng/mL at both baseline and year 2) increased the hazard of the composite kidney endpoint (HR, 1.61; 95% CI, 1.07-2.42; P = 0.09) after adjusting for covariates. The relationship of persistently elevated MMP-2 was modified by levels of inflammation, with a 2.6 times higher rate of the composite kidney endpoint in those with high-sensitivity C-reactive protein < 2.5 g/dL at study entry. Heterogeneity of effect was found with proteinuria, with a baseline MMP-2 level of ≥300 ng/mL associated with an increased risk of the composite kidney endpoint (HR, 1.30; 95% CI, 1.09-1.54) only with proteinuria ≥ 442 mg/g. Limitations: The observational study design limits causal interpretation. Conclusions: Elevated MMP-2 is associated with CKD progression, particularly among those with low inflammation and those with proteinuria. Future investigations are warranted to confirm the reduction in risk of CKD progression among these subgroups of patients with CKD.

Matrix metalloproteinase 2 (MMP-2) is a matrix-degrading protease involved in fibrosis and elevated in chronic kidney disease (CKD). Longitudinal patterns of MMP-2 have not previously been assessed as a predictor of CKD progression in a large prospective cohort. Here, we found that a higher baseline level and an increasing or persistently elevated 2-year pattern of MMP-2 were associated with CKD progression, independent of all covariates except proteinuria. The association of baseline MMP-2 with CKD progression differed by level of proteinuria, whereas levels of inflammation modified the associations of 2-year MMP-2 patterns with CKD progression.