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Background Acute-on-chronic kidney disease (ACKD) is poorly understood and often overlooked. We studied its incidence, circumstances, determinants and outcomes in patients with CKD. Methods We used the Kidney Disease: Improving Global Outcomes criteria to identify all-stage acute kidney injury (AKI) events in 3033 nephrology outpatients with CKD Stages 3–5 participating in the CKD-Renal Epidemiology and Information Network cohort study (2013–20), and cause-specific Cox models to estimate hazard ratios [HRs; 95% confidence intervals (CIs)] of AKI-associated risk factors. Results At baseline, 22% of the patients [mean age 67 years, 65% men, mean estimated glomerular filtration rate (eGFR) 32 mL/min/1.73 m2] had a history of AKI. Over a 3-year follow-up, 443 had at least one AKI event: 27% were Stage 2 or 3 and 11% required dialysis; 74% involved hospitalization including 47% acquired as hospital inpatients; and a third were not reported in hospital discharge reports. Incidence rates were 10.1 and 4.8/100 person-years in patients with and without an AKI history, respectively. In 2375 patients without this history, male sex, diabetes, cardiovascular disease, cirrhosis, several drugs, low eGFR and serum albumin levels were significantly associated with a higher risk of AKI, as were low birth weight ( Conclusions The study highlights the high rate of hospital-acquired AKI events in patients with CKD, and their underreporting at hospital discharge. It also reveals low birth weight and anaemia as possible new risk factors in CKD patients.

BACKGROUND AND AIMS Elevated serum urea levels are common in moderate-to-advanced CKD. Several studies have shown that urea is a direct and indirect uremic toxin, especially with regard to cardiovascular disease. We sought to determine whether serum urea levels are associated with adverse cardiovascular events and death before kidney replacement therapy (KRT) in patients with CKD. METHOD CKD-REIN is a prospective cohort of CKD nephrology outpatients not receiving maintenance dialysis. The 2507 patients included in the analysis were divided into three groups according to the baseline serum urea level (T1 RESULTS Of the 2507 included patients {median [first quartile–third quartile (Q1–Q3)] age: 69 (61–77); mean (standard deviation) eGFR 33.5(11.6) mL/min/1.73 m²}, 54% had a history of cardiovascular disease. Over a median follow-up of 3.0 years [Q1–Q3, 2.2–3.1], 451 experienced their first atheromatous or nonatheromatous cardiovascular event (fatal or nonfatal), leading to an incidence rate (IR) [95% confidence interval (95% CI)] of 7.1 (6.4–7.7)/100 person-years (PYs) (Fig. 1). Over a median follow-up period of 4.8 (3.3–5.1) years, 407 patients died before KRT, leading to an IR of 4.0 (3.6–4.3)/100 PYs. After multiple adjustments for cardiovascular risk factors (including eGFR), patients in T3 had a higher risk of atheromatous and nonatheromatous cardiovascular events than patients in T1 [HR (95% CI), 2.08 (1.50–2.88), Fig. 1]. A nonsignificant trend towards a higher risk was also noted for patients in T2 [1.28 (0.96–1.71)]. The adjusted HRs for death before KRT were 1.30 (0.96–1.75] and 1.73 (1.22–2.45) for patients in T2 and those in T3, respectively. CONCLUSION Beyond CV risk factors including eGFR, this hypothesis-generating study suggests that serum urea level is a predictor of cardiovascular outcomes in patients with moderate to advanced CKD. Further research is needed to confirm current findings and explore mechanisms.

Background and Aims The use of oral antithrombotics in patients with chronic kidney disease (CKD) is challenging because of altered pharmacodynamics/pharmacokinetics. Patients prescribed oral anticoagulant are at high risk of bleeding, and possibly also acute kidney injury (AKI) and progression to kidney failure. We assessed bleeding, AKI, and kidney failure risks associated with oral anticoagulant and/or antiplatelet agent prescription in patients with moderate-to-advanced CKD. Method CKD-REIN is a prospective cohort of 3022 nephrology outpatients with CKD stages 2-5 at inclusion. Drug prescriptions and their duration were collected prospectively. We used cause-specific Cox proportional hazard models to estimate hazard ratios (HR) for bleeding (identified through hospitalizations), AKI (as defined according to KDIGO 2012), and kidney failure. Prescriptions of oral antithrombotics were treated as a time dependent variable and models were adjusted for baseline comorbidities, laboratory data, and other medications. Results At baseline, 339 (11%) patients (65% men; median age 69 [interquartile range (IQR), 60-76] years; median eGFR 32 [IQR, 23-41] were prescribed oral anticoagulants only, 1095 (36%) antiplatelet only, and 101 (3%) both anticoagulant and antiplatelet. Over a median follow-up of 3 years (IQR, 2.8-3.1), 152 patients experienced a bleeding event requiring hospital visit/stay (crude incidence rate (IR): 1.9% person-years [95%CI,1.6-2.2]), 414 patients experienced AKI (crude IR: 5.4 % person-years [4.9-5.9]), and 270 experienced kidney failure (crude IR: 3.4 % person-years [3.0-3.8]). A significant interaction was found between oral antithrombotics and eGFR (interaction p=0.03). The adjusted HRs [95%CI] for bleeding associated with prescriptions of antiplatelets only, oral anticoagulants only, and antiplatelet + oral anticoagulant were respectively 0.58 [0.30; 1.11], 2.62 [1.39; 4.93], and 5.76 [2.85; 11.66] in patients with a baseline eGFR < 30 mL/min/1.73m2. In patients with baseline eGFR ≥ 30 mL/min/1.73m2, the adjusted HRs [95%CI] for bleeding associated with prescriptions of antiplatelets only, oral anticoagulants .......only, and antiplatelet + oral anticoagulant were respectively 0.98 [0.48; 1.98], 1.91 [0.87; 4.20], and 1.54 [0.46; 5.12] (Figure 1A). An increased risk of AKI risk was associated with the prescription of oral anticoagulants (adjusted HR [95%CI]: 1.91[1.48; 2.46]) but not the prescription of antiplatelets (1.24[0.98; 1.56], Figure 1B). No significant interactions were found between oral anticoagulants and eGFR or antiplatelet agents. Kidney failure was not associated with the prescription of oral antithrombotics of any type (Figure 1C). No significant interactions were found with eGFR and antiplatelet agents. Conclusion This study confirms the risk of AKI in CKD patients prescribed oral anticoagulants. It also highlights the potential aggravating effect of combining anticoagulants and antiplatelet on the risk of bleeding in this population.

Background and Aims The association between hyperuricemia and CKD progression is not well established in Europe and, to our knowledge, has not yet been investigated using longitudinal measurements. Method We used data from CKD-REIN, a prospective cohort study conducted in 40 representative French nephrology clinics, which included 3033 patients with CKD stages 3 to 5 between 2013 and 2016. Patients who had no serum uric acid or no creatinine measure at within 6 months of their inclusion date in the CKD-REIN study were excluded. All uric acid measures were taken into account, from inclusion to the occurrence of renal replacement therapy (RRT), death, or end of follow-up, whichever came first. We used a shared random-effect model for the joint analysis of individual trajectories of uric acid and the hazard of the composite outcome (RRT or death before RRT) and each specific event separately. Hazard ratio were adjusted (aHR) for age, sex, primary kidney disease, metabolic syndrome, cardiovascular disease, proteinuria (< 30, 30-300, > 300 mg/day), and the CKD-EPI estimated glomerular filtration rate (eGFR) at baseline. In a sensitivity analysis, we further adjusted for individual eGFR trajectory. Results A total of 2781 patients (65.5% men, median age 69 years) were included. At baseline, the median eGFR was 31.8 mL/min/1.73m2 and the median uric acid value was 425 µmol/L. During a median follow-up of 3.2 years, 434 patients received RRT and 264 died before RRT. At any time of follow-up, an increase of 100 µmol/l of the current value of uric acid was associated with a 16% increased hazard of RRT or death before RRT (aHR 1.16, 95% CI 1.07-1.26). The estimated effect of uric acid was similar with RRT (aHR 1.18, 95% CI 1.04-1.34) and death before RRT (aHR 1.16, 95% CI 1.05-1.28). When further adjusted for eGFR trajectory, the estimated effect of uric acid on the composite outcome was much weaker (aHR 1.06, 95% CI 0.98-1.16). Conclusion A higher current level of uric acid is associated with a strong increase in the hazard of RRT or death before RRT in European patients with CKD stage 3 to 5. However, the association is much weaker after adjustment for eGFR trajectory. Further analyses are necessary to better understand the dynamic of the association between uric acid and GFR.

Background and Aims Metabolic acidosis is a common complication of CKD and may contribute to CKD progression. However, the association between serum bicarbonate and CKD progression has not yet been investigated using longitudinal measurements. Method We used data from CKD-REIN, a prospective cohort study conducted in 40 representative French nephrology clinics which included 3033 patients with CKD stages 3 to 5 between 2013 and 2016. Patients who had no serum bicarbonate or no creatinine measure at within 6 months of their inclusion date in the CKD-REIN study were excluded. All serum bicarbonate measurements were taken into account, from inclusion to the occurrence of renal replacement therapy (RRT), death, or end of follow-up, whichever came first. We used a shared random-effect model for the joint analysis of individual trajectories of serum bicarbonate and the hazard of the composite outcome (RRT or death before RRT) and each specific event separately. Hazard ratio were adjusted (aHR) for age, sex, primary kidney disease, metabolic syndrome, cardiovascular disease, proteinuria (< 30, 30-300, > 300 mg/day), and the CKD-EPI estimated glomerular filtration rate (eGFR) at baseline. Results A total of 2977 patients (65.4% men, median age 69 years) were included. At baseline, the median eGFR was 31.8 mL/min/1.73m2 and the median bicarbonate concentration was 25 mmol/L. During a median follow-up of 4.5 years, 615 patients received RRT and 378 died before RRT. At any time of follow-up, a decrease of 1 mmol/l of the current level of serum bicarbonate was associated with a significantly increased hazard of RRT or death before RRT (aHR 1.05, 95%CI 1.02-1.08). The estimated effect was stronger on death before RRT (aHR 1.05, 95% CI 1.00-1.09) than on RRT (aHR 1.02, 95% CI 0.99-1.06). Conclusion A lower current level of serum bicarbonate is associated with an increased mortality in patients with CKD stage 3 to 5.

Muscle wasting predicts mortality in patients with end-stage renal disease (ESRD), but its role in the progression of chronic kidney disease (CKD) is uncertain. We studied CKD outcomes associated with low muscle mass, assessed by urinary creatinine excretion (UCr).The NephroTest cohort included 1429 patients with CKD stages 1-4 and both measured glomerular filtration rate (mGFR) (by (51)Cr-EDTA) and estimated glomerular filtration rate (eGFR) (by CKD-Epidemiology Collaboration equation). We used cause-specific Cox models to estimate hazard ratios (HRs) for the competing risks of ESRD and death associated with gender-specific UCr quartiles.UCr was 13.6 ± 3.2 mmol/24 h (0.17 ± 0.05 mmol/kg/24 h) in men and 9.2 ± 2.1 (0.14 ± 0.05) in women. It was positively associated with mGFR, but not with eGFR. Over a median follow-up of 3.6 (2.1-5.8) years, 229 patients developed ESRD and 113 patients died before ESRD. Compared with patients in the highest UCr quartile, those in the lowest quartile had a higher crude HR (95% confidence interval) for pre-ESRD death: 4.3 (2.4-7.7), which was weakened, but remained statistically significant, independent of demographics, mGFR and several other factors: 2.1 (1.04-4.3). Their crude ESRD risk was not higher: HR: 0.95 (0.65-1.4), and even tended to be lower after adjusting for mGFR and log-proteinuria: HR: 0.70 (0.45-1.1). Adjustment for eGFR instead of mGFR reversed this relationship: HR: 1.7 (1.1-2.7).In early stage CKD, low UCr is associated with higher risk for mortality, but not for ESRD. Using creatinine-based equation to adjust for GFR may bias the relationship of UCr with ESRD risk.

Background Renal function in patients with chronic kidney disease (CKD) may follow different trajectory profiles. The aim of this study was to evaluate and illustrate the ability of the latent class linear mixed model (LCMM) to identify clinically relevant subgroups of renal function trajectories within a multicenter hospital-based cohort of CKD patients. Methods We analysed data from the NephroTest cohort including 1967 patients with all-stage CKD at baseline who had glomerular filtration rate (GFR) both measured by 51 Cr-EDTA renal clearance (mGFR) and estimated by the CKD-EPI equation (eGFR); 1103 patients had at least two measurements. The LCMM was used to identify subgroups of GFR trajectories, and patients' characteristics at baseline were compared between the subgroups identified. Results Five classes of mGFR trajectories were identified. Three had a slow linear decline of mGFR over time at different levels. In the two others, patients had a high level of mGFR at baseline with either a strong nonlinear decline over time ( n = 11) or a nonlinear improvement ( n = 94) of mGFR. Higher levels of proteinuria and blood pressure at baseline were observed in classes with either severely decreased mGFR or strong mGFR decline over time. Using eGFR provided similar findings. Conclusion The LCMM allowed us to identify in our cohort five clinically relevant subgroups of renal function trajectories. It could be used in other CKD cohorts to better characterize their different profiles of disease progression, as well as to investigate specific risk factors associated with each profile.