Target Trial Emulation: A Call for More Widespread Use.

Causal inference methods intended for use with observational data have been widely available for decades, but barriers exist to their widespread adoption. These likely include lack of familiarity with several methodologic techniques often used in combination in these investigations such as inverse probability of treatment weighting and g-estimation, and the intensity of computational effort to employ these techniques. Even with these methods, critical design flaws undermine the ability to make valid causal inference in some studies.

Fibroblast Growth Factor 23 and Risk of Heart Failure Subtype: The CRIC (Chronic Renal Insufficiency Cohort) Study.

Rationale & Objective: Heart failure (HF) is an important cause of morbidity and mortality among individuals with chronic kidney disease (CKD). A large body of evidence from preclinical and clinical studies implicates excess levels of fibroblast growth factor 23 (FGF23) in HF pathogenesis in CKD. It remains unclear whether the relationship between elevated FGF23 levels and HF risk among individuals with CKD varies by HF subtype.

Association of urine and plasma ADMA with atherosclerotic risk in DKD cardiovascular disease risk in diabetic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) study.

Background: Chronic kidney disease (CKD) is associated with atherosclerotic cardiovascular disease (ASCVD) risk, especially among those with diabetes. Altered metabolism of solutes that accumulate in CKD [asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and trimethylamine N-oxide (TMAO)] may reflect pathways linking CKD with ASCVD.

Methods: This case-cohort study included Chronic Renal Insufficiency Cohort participants with baseline diabetes, estimated glomerular filtration rate <60 mL/min/1.

Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

Background: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals.

Methods: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.

Association of early hypotension in pediatric sepsis with development of new or persistent acute kidney injury.

Objective: To determine how hypotension in the first 48 h of sepsis management impacts acute kidney injury (AKI) development and persistence.

Study Design: Retrospective study of patients > 1 month to < 20 years old with sepsis in a pediatric ICU between November 2012 and January 2015 (n = 217). All systolic blood pressure (SBP) data documented within 48 h after sepsis recognition were collected and converted to percentiles for age, sex, and height.

Longitudinal Evolution of Markers of Mineral Metabolism in Patients With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

Rationale & Objective: The pathogenesis of disordered mineral metabolism in chronic kidney disease (CKD) is largely informed by cross-sectional studies of humans and longitudinal animal studies. We sought to characterize the longitudinal evolution of disordered mineral metabolism during the course of CKD.

Study Design: Retrospective analysis nested in a cohort study.

Risk factors and inpatient outcomes associated with acute kidney injury at pediatric severe sepsis presentation.

Background: Little data exist on acute kidney injury (AKI) risk factors in pediatric sepsis. We identified risk factors and inpatient outcomes associated with AKI at sepsis recognition in children with severe sepsis.

Methods: Retrospective, cross-sectional study with inpatient outcome description of 315 patients > 1 month to < 20 years old with severe sepsis in a pediatric intensive care unit over 3 years.

Association of Pulse Wave Velocity With Chronic Kidney Disease Progression and Mortality: Findings From the CRIC Study (Chronic Renal Insufficiency Cohort).

Patients with chronic kidney diseases (CKDs) are at risk for further loss of kidney function and death, which occur despite reasonable blood pressure treatment. To determine whether arterial stiffness influences CKD progression and death, independent of blood pressure, we conducted a prospective cohort study of CKD patients enrolled in the CRIC study (Chronic Renal Insufficiency Cohort). Using carotid-femoral pulse wave velocity (PWV), we examined the relationship between PWV and end-stage kidney disease (ESRD), ESRD or halving of estimated glomerular filtration rate, or death from any cause.

Statistical Methods for Recurrent Event Analysis in Cohort Studies of CKD.

Cardiovascular events, such as hospitalizations because of congestive heart failure, often occur repeatedly in patients with CKD. Many studies focus on analyses of the first occurrence of these events, and discard subsequent information. In this article, we review a number of statistical methods for analyzing ordered recurrent events of the same type, including Poisson regression and three commonly used survival models that are extensions of Cox proportional hazards regression.

Statistical Methods for Cohort Studies of CKD: Survival Analysis in the Setting of Competing Risks.

Survival analysis is commonly used to evaluate factors associated with time to an event of interest ( ESRD, cardiovascular disease, and mortality) among CKD populations. Time to the event of interest is typically observed only for some participants. Other participants have their event time censored because of the end of the study, death, withdrawal from the study, or some other competing event.

Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease.

Inflammation is a consequence of chronic kidney disease (CKD) and is associated with adverse outcomes in many clinical settings. Inflammation stimulates production of fibroblast growth factor 23 (FGF23), high levels of which are independently associated with mortality in CKD. Few large-scale prospective studies have examined inflammation and mortality in patients with CKD, and none tested the interrelationships among inflammation, FGF23, and risk of death.

Genome-Wide Association of CKD Progression: The Chronic Renal Insufficiency Cohort Study.

The rate of decline of renal function varies significantly among individuals with CKD. To understand better the contribution of genetics to CKD progression, we performed a genome-wide association study among participants in the Chronic Renal Insufficiency Cohort Study. Our outcome of interest was CKD progression measured as change in eGFR over time among 1331 blacks and 1476 whites with CKD.

Serum β-Trace Protein and β2-Microglobulin as Predictors of ESRD, Mortality, and Cardiovascular Disease in Adults With CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study.

Background: Serum β-trace protein (BTP) and β2-microglobulin (B2M) are independently associated with end-stage renal disease (ESRD) and mortality in the general population and high-risk groups with diabetes or advanced chronic kidney disease (CKD). Less is known about their associations with outcomes and predictive ability in adults with moderate CKD.

Study Design: Prospective cohort study.

Change in Measured GFR Versus eGFR and CKD Outcomes.

Measured GFR (mGFR) has long been considered the gold standard measure of kidney function, but recent studies have shown that mGFR is not consistently superior to eGFR in explaining CKD-related comorbidities. The associations between longitudinal changes in mGFR versus eGFR and adverse outcomes have not been examined. We analyzed a subset of 942 participants with CKD in the Chronic Renal Insufficiency Cohort Study who had at least two mGFRs and two eGFRs determined concurrently by iothalamate and creatinine (eGFRcr) or cystatin C, respectively.

High-sensitivity troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and risk of incident heart failure in patients with CKD: the Chronic Renal Insufficiency Cohort (CRIC) Study.

High-sensitivity troponin T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) strongly predict heart failure (HF) in the general population. However, the interpretation of levels of these biomarkers as predictors of HF is uncertain among patients with CKD. Here, we investigated whether hsTnT and NT-proBNP are associated with incident HF among patients with CKD.

Relation of serum lipids and lipoproteins with progression of CKD: The CRIC study.

Background And Objectives: Hyperlipidemia is common in patients with CKD. The objective of this study was to evaluate whether measures of plasma lipids and lipoproteins predict progression of kidney disease in patients with CKD.

Design, Setting, Participants, & Measurements: Prospective cohort study in adults (n=3939) with CKD aged 21-74 years recruited between 2003 and 2008 and followed for a median of 4.

Fibroblast growth factor-23 and cardiovascular events in CKD.

An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44±15 ml/min per 1.

Estimating GFR among participants in the Chronic Renal Insufficiency Cohort (CRIC) Study.

Background: Glomerular filtration rate (GFR) is considered the best measure of kidney function, but repeated assessment is not feasible in most research studies.

Study Design: Cross-sectional study of 1,433 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study (ie, the GFR subcohort) to derive an internal GFR estimating equation using a split-sample approach.

Setting & Participants: Adults from 7 US metropolitan areas with mild to moderate chronic kidney disease; 48% had diabetes and 37% were black.

Earlier onset and greater severity of disordered mineral metabolism in diabetic patients with chronic kidney disease.

Objective: Disordered mineral metabolism is a common complication of chronic kidney disease (CKD) and a novel risk factor for CKD progression, cardiovascular disease, and mortality. Although diabetes is the leading cause of CKD and is associated with worse clinical outcomes than other etiologies, few studies have evaluated mineral metabolism in CKD according to diabetes status.

Research Design And Methods: Using the Chronic Renal Insufficiency Cohort Study, we tested the hypothesis that diabetes is independently associated with lower serum calcium and higher serum phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23).

Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.

Context: A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is associated with mortality in patients with end-stage renal disease, but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease.

Objective: To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease.

Design, Setting, And Participants: A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008.

Diuretics, calciuria and secondary hyperparathyroidism in the Chronic Renal Insufficiency Cohort.

Background: Secondary hyperparathyroidism is a common complication of chronic kidney disease (CKD) that is associated with bone disease, cardiovascular disease and death. Pathophysiological factors that maintain secondary hyperparathyroidism in advanced CKD are well-known, but early mechanisms of the disease that can be targeted for its primary prevention are poorly understood. Diuretics are widely used to control volume status and blood pressure in CKD patients but are also known to have important effects on renal calcium handling, which we hypothesized could alter the risk of secondary hyperparathyroidism.