Faculty Bibliography

BACKGROUND AND OBJECTIVES:kidney disease risk variants, over and above iodine-125 iothalamate measured GFR and proteinuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Using data from the African-American Study of Kidney Disease and Hypertension, a multicenter clinical trial followed by a cohort phase with a median total follow-up of 9.7 years (interquartile range, 6.5-10.9 years), we examined the associations of suPAR with CKD progression (defined as doubling of serum creatinine or ESKD), ESKD, worsening proteinuria (defined as pre-ESKD doubling of 24-hour urine protein-to-creatinine ratio to ≥220 mg/g), and all-cause death. RESULTS:=0.02). CONCLUSIONS:kidney disease risk variants, independently of proteinuria and GFR.

BACKGROUND AND OBJECTIVES:All randomized trials of direct oral anticoagulants in atrial fibrillation excluded patients with severe kidney disease. The safety and effectiveness of direct oral anticoagulants across the range of eGFR in real-world settings is unknown. Our objective is to quantify the risk of bleeding and benefit of ischemic stroke prevention for direct oral anticoagulants compared with warfarin in patients with atrial fibrillation with and without CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:). RESULTS:-interaction=0.70). Similar findings were observed with individual drugs. CONCLUSIONS:who took direct oral anticoagulants for atrial fibrillation had slightly higher risk of bleeding compared with those on warfarin, but similar benefits from prevention of ischemic stroke.

Chronic kidney disease (CKD) involves significant metabolic abnormalities and has a high mortality rate. Because the levels of serum metabolites in patients with CKD might provide insight into subclinical disease states and risk for future mortality, we determined which serum metabolites reproducibly associate with mortality in CKD using a discovery and replication design. Metabolite levels were quantified via untargeted liquid chromatography and mass spectroscopy from serum samples of 299 patients with CKD in the Modification of Diet in Renal Disease (MDRD) study as a discovery cohort. Six among 622 metabolites were significantly associated with mortality over a median follow-up of 17 years after adjustment for demographic and clinical covariates, including urine protein and measured glomerular filtration rate. We then replicated associations with mortality in 963 patients with CKD from the African American Study of Kidney Disease and Hypertension (AASK) cohort over a median follow-up of ten years. Three of the six metabolites identified in the MDRD cohort replicated in the AASK cohort: fumarate, allantoin, and ribonate, belonging to energy, nucleotide, and carbohydrate pathways, respectively. Point estimates were similar in both studies and in meta-analysis (adjusted hazard ratios 1.63, 1.59, and 1.61, respectively, per doubling of the metabolite). Thus, selected serum metabolites were reproducibly associated with long-term mortality in CKD beyond markers of kidney function in two well characterized cohorts, providing targets for investigation.

Aims:Both hypo- and hyperkalaemia can have immediate deleterious physiological effects, and less is known about long-term risks. The objective was to determine the risks of all-cause mortality, cardiovascular mortality, and end-stage renal disease associated with potassium levels across the range of kidney function and evaluate for consistency across cohorts in a global consortium. Methods and results:We performed an individual-level data meta-analysis of 27 international cohorts [10 general population, 7 high cardiovascular risk, and 10 chronic kidney disease (CKD)] in the CKD Prognosis Consortium. We used Cox regression followed by random-effects meta-analysis to assess the relationship between baseline potassium and adverse outcomes, adjusted for demographic and clinical characteristics, overall and across strata of estimated glomerular filtration rate (eGFR) and albuminuria. We included 1 217 986 participants followed up for a mean of 6.9 years. The average age was 55 ± 16 years, average eGFR was 83 ± 23 mL/min/1.73 m2, and 17% had moderate- to-severe increased albuminuria levels. The mean baseline potassium was 4.2 ± 0.4 mmol/L. The risk of serum potassium of >5.5 mmol/L was related to lower eGFR and higher albuminuria. The risk relationship between potassium levels and adverse outcomes was U-shaped, with the lowest risk at serum potassium of 4-4.5 mmol/L. Compared with a reference of 4.2 mmol/L, the adjusted hazard ratio for all-cause mortality was 1.22 [95% confidence interval (CI) 1.15-1.29] at 5.5 mmol/L and 1.49 (95% CI 1.26-1.76) at 3.0 mmol/L. Risks were similar by eGFR, albuminuria, renin-angiotensin-aldosterone system inhibitor use, and across cohorts. Conclusions:Outpatient potassium levels both above and below the normal range are consistently associated with adverse outcomes, with similar risk relationships across eGFR and albuminuria.

Importance:Approximately 1 million patients in the United States with type 2 diabetes mellitus and mild-to-moderate kidney disease do not receive guideline-directed therapy with metformin. This may reflect uncertainty regarding the risk of acidosis in patients with chronic kidney disease. Objective:To quantify the association between metformin use and hospitalization with acidosis across the range of estimated glomerular filtration rate (eGFR), accounting for change in eGFR stage over time. Design, Setting, and Participants:Community-based cohort of 75 413 patients with diabetes in Geisinger Health System, with time-dependent assessment of eGFR stage from January 2004 until January 2017. Results were replicated in 67 578 new metformin users and 14 439 new sulfonylurea users from 2010 to 2015, sourced from 350 private US health systems. Exposures:Metformin use. Main Outcomes and Measures:Hospitalization with acidosis (International Classification of Diseases, Ninth Revision, Clinical Modification code of 276.2). Results:In the primary cohort (n = 75 413), mean (SD) patient age was 60.4 (15.5) years, and 51% (n = 38 480) of the participants were female. There were 2335 hospitalizations with acidosis over a median follow-up of 5.7 years (interquartile range, 2.5-9.9 years). Compared with alternative diabetes management, time-dependent metformin use was not associated with incident acidosis overall (adjusted hazard ratio [HR], 0.98; 95% CI, 0.89-1.08) or in patients with eGFR 45 to 59 mL/min/1.73 m2 (adjusted HR, 1.16; 95% CI, 0.95-1.41) and eGFR 30 to 44 mL/min/1.73 m2 (adjusted HR, 1.09; 95% CI, 0.83-1.44). On the other hand, metformin use was associated with an increased risk of acidosis at eGFR less than 30 mL/min/1.73 m2 (adjusted HR, 2.07; 95% CI, 1.33-3.22). Results were consistent when new metformin users were compared with new sulfonylurea users (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 0.77; 95% CI, 0.29-2.05), in a propensity-matched cohort (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 0.71; 95% CI, 0.45-1.12), when baseline insulin users were excluded (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 1.16; 95% CI, 0.87-1.57), and in the replication cohort (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 0.86; 95% CI, 0.37-2.01). Conclusions and Relevance:In 2 real-world clinical settings, metformin use was associated with acidosis only at eGFR less than 30 mL/min/1.73 m2. Our results support cautious use of metformin in patients with type 2 diabetes and eGFR of at least 30 mL/min/1.73 m2.

BACKGROUND:In people with chronic kidney disease (CKD), HbA1c may be a problematic measure of glycemic control. Glycated albumin and fructosamine have been proposed as better markers of hyperglycemia in CKD. In the present study we investigated associations of HbA1c, glycated albumin, and fructosamine with fasting glucose by CKD categories. METHODS:A cross-sectional analysis was performed of 1665 Atherosclerosis Risk in Communities Study participants with diagnosed diabetes aged ≥65 years. Spearman's rank correlations (r) were compared and Deming regression was used to obtain root mean square errors (RMSEs) for the associations across CKD categories defined using estimated glomerular filtration rate and urine albumin:creatinine ratio. RESULTS:Correlations of HbA1c, glycated albumin, and fructosamine with fasting glucose were lowest in people with severe CKD (HbA1c r = 0.52, RMSE = 0.91; glycated albumin r = 0.39, RMSE = 1.89; fructosamine r = 0.41, RMSE = 1.87) and very severe CKD (r = 0.48 and RMSE = 1.01 for HbA1c; r = 0.36 and RMSE = 2.14 for glycated albumin; r = 0.36 and RMSE = 2.22 for fructosamine). Associations of glycated albumin and fructosamine with HbA1c were relatively similar across CKD categories. CONCLUSIONS:In older adults with severe or very severe CKD, HbA1c, glycated albumin, and fructosamine were not highly correlated with fasting glucose. The results suggest there may be no particular advantage of glycated albumin or fructosamine over HbA1c for monitoring glycemic control in CKD.

BACKGROUND:Reduced estimated glomerular filtration rate (eGFR) and elevated urinary albumin-to-creatinine ratio (ACR) individually increase risk of cardiovascular disease (CVD). We hypothesized that these associations are stronger among people with abnormal (both low and high) hemoglobin levels. METHODS AND RESULTS:-for-interaction, 0.074). CONCLUSIONS:Kidney function, albuminuria, and anemia were correlated and independently associated with CVD risk. Correlation and potential interaction for atherosclerotic CVD between albuminuria and high hemoglobin deserve further investigation.

BACKGROUND AND AIMS:Despite its strong link to cardiovascular outcomes, the association of chronic kidney disease (CKD) with abdominal aortic aneurysm (AAA) has not been explicitly and comprehensively investigated. METHODS:In 10,724 participants in the Atherosclerosis Risk in Communities Study (aged 53-75 years during 1996-1998), we evaluated the associations of two key CKD measures - estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR) - with incident AAA (AAA diagnosis in outpatient, hospitalization discharge, or death records). Additionally, we performed a cross-sectional analysis for the CKD measures and ultrasound-based abdominal aortic diameter in 4258 participants during 2011-2013. RESULTS:and was 2.49 (1.28-4.87) for ACR ≥300, 1.99 (1.40-2.83) for 30-299, and 1.46 (1.08-1.97) for 10-29 compared to ACR <10 mg/g. The associations were generally similar after accounting for additional confounders, such as smoking (although attenuated), or after stratifying by subgroups, including diabetes. The cross-sectional analysis also showed continuous positive associations of these CKD measures with aortic diameter, particularly at the distal aortic segment assessed. CONCLUSIONS:Reduced eGFR and elevated albuminuria were independently associated with greater incidence of AAA and greater abdominal aortic diameter. Our results suggest the potential usefulness of CKD measures to identify persons at high risk of AAA and the need to investigate pathophysiological pathways linking CKD to AAA.