Chronic Renal Insufficiency Cohort Research Articles

Associations Between Cardiac Biomarkers and Cardiac Structure and Function in CKD

IntroductionSubclinical changes to cardiac structure and function detected with echocardiography precede the development of clinical heart failure (HF) in persons with chronic kidney disease (CKD). Circulating cardiac biomarkers may reflect these pathophysiological changes. This study investigated associations between established biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP] and high-sensitivity troponin T [hsTnT]) and novel biomarkers (growth differentiation factor 15 [GDF-15], galectin-3 [Gal-3], and soluble ST-2 [sST-2]), using echocardiographic measurements in persons with CKD.MethodsIn cross-sectional analyses among 2101 participants with mild to moderate CKD in the Chronic Renal Insufficiency Cohort (CRIC), biomarker levels measured at baseline were evaluated with echocardiographic measurements 1 year later. These included left ventricular mass index (LVMI), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), left ventricular ejection fraction (LVEF), and left atrial diameter (LAD). Multivariable linear regression analyses tested associations of each biomarker with echocardiographic measurements, adjusting for covariates.ResultsGDF-15 was significantly associated with higher LVMI (1.0 g/m2.7; 95% CI, 0.4–1.7), LVESV (0.4 ml/m2.7; 95% CI, 0.0–0.7), and LVEDV (0.6 ml/m2.7; 95% CI, 0.1–1.1), but not with LVEF or LAD. These findings were not significant when adjusting for NT-proBNP and hsTnT. Gal-3 and sST-2 had no significant associations. Higher levels of NT-proBNP and hsTnT were associated with all echocardiographic measurements.ConclusionIn patients with CKD, the novel biomarker GDF-15, a marker of inflammation and tissue injury, and clinical biomarkers NT-proBNP and hsTnT, were associated with echocardiographic measurements of subclinical cardiovascular disease. Collectively, these biomarkers may highlight biological pathways that contribute to the development of clinical HF.

Metabolomic Markers of Kidney Function Decline in Patients With Diabetes: Evidence From the Chronic Renal Insufficiency Cohort (CRIC) Study

Biomarkers that provide reliable evidence of future diabetic kidney disease (DKD) are needed to improve disease management. In a cross-sectional study, we previously identified 13 urine metabolites that had levels reduced in DKD compared with healthy controls. We evaluated associations of these 13 metabolites with future DKD progression. Prospective cohort. 1,001 Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes with estimated glomerular filtration rates (eGFRs) between 20 and 70mL/min/1.73m2 were followed up prospectively for a median of 8 (range, 2-10) years. 13 urine metabolites, age, race, sex, smoked more than 100 cigarettes in lifetime, body mass index, hemoglobin A1c level, blood pressure, urinary albumin, and eGFR. Annual eGFR slope and time to incident kidney failure with replacement therapy (KFRT; ie, initiation of dialysis or receipt of transplant). Several clinical metabolite models were developed for eGFR slope as the outcome using stepwise selection and penalized regression, and further tested on the time-to-KFRT outcome. A best cross-validated (final) prognostic model was selected based on high prediction accuracy for eGFR slope and high concordance statistic for incident KFRT. During follow-up, mean eGFR slope was-1.83±1.92 (SD) mL/min/1.73m2 per year; 359 (36%) participants experienced KFRT. Median time to KFRT was 7.45 years from the time of entry to the CRIC Study. In our final model, after adjusting for clinical variables, levels of metabolites 3-hydroxyisobutyrate (3-HIBA) and 3-methylcrotonyglycine had a significant negative association with eGFR slope, whereas citric and aconitic acid were positively associated. Further, 3-HIBA and aconitic acid levels were associated with higher and lower risk for KFRT, respectively (HRs of 2.34 [95% CI, 1.51-3.62] and 0.70 [95% CI, 0.51-0.95]). Subgroups for whom metabolite signatures may not be optimal, nontargeted metabolomics by flow-injection analysis, and 2-stage modeling approaches. Urine metabolites may offer insights into DKD progression. If replicated in future studies, aconitic acid and 3-HIBA could identify individuals with diabetes at high risk for GFR decline, potentially leading to improved clinical care and targeted therapies.

Association of Opioids and Nonsteroidal Anti-inflammatory Drugs With Outcomes in CKD: Findings From the CRIC (Chronic Renal Insufficiency Cohort) Study

Safe analgesic choices are limited in chronic kidney disease (CKD). We conducted a comparative analysis of harm from opioids versus nonsteroidal anti-inflammatory drugs (NSAIDs) in CKD. Prospective cohort study. 3,939 patients with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study. 30-day analgesic use reported at annual visits. A composite outcome of 50% glomerular filtration rate reduction and kidney failure requiring kidney replacement therapy (KRT), as well as the outcomes of kidney failure requiring KRT, hospitalization, and pre-kidney failure death. Marginal structural models with time-updated exposures. Participants were followed up for a median of 6.84 years, with 391 (9.9%) and 612 (15.5%) reporting baseline opioid and NSAID use, respectively. Time-updated opioid use was associated with the kidney disease composite outcome, kidney failure with KRT, death (HRs of 1.4 [95% CI, 1.2-1.7], 1.4 [95% CI, 1.1-1.7], and 1.5 [95% CI, 1.2-2.0], respectively), and hospitalization (rate ratio [RR], 1.7; 95% CI, 1.6-1.9) versus opioid nonusers. Similar results were found in an analysis restricted to a subcohort of participants reporting ever using other (nonopioid and non-NSAID) analgesics or tramadol. Time-updated NSAID use was associated with increased risk for the kidney disease composite (HR, 1.2; 95% CI, 1.0-1.5) and hospitalization (RR, 1.1; 95% CI, 1.0-1.3); however, these associations were not significant in the subcohort. The association of NSAID use with the kidney disease composite outcome varied by race, with a significant risk in blacks (HR, 1.3; 95% CI, 1.0-1.7). NSAID use was associated with lower risk for kidney failure with KRT in women and individuals with glomerular filtration rate<45mL/min/1.73m2 (HRs of 0.63 [95% CI, 0.45-0.88] and 0.77 [95% CI, 0.59-0.99], respectively). Limited periods of recall of analgesic use and potential confounding by indication. Opioid use had a stronger association with adverse events than NSAIDs, with the latter's association with kidney disease outcomes limited to specific subgroups, notably those of black race.

Association of 24-Hour Ambulatory Blood Pressure Patterns with Cognitive Function and Physical Functioning in CKD.

Hypertension is highly prevalent in patients with CKD as is cognitive impairment and frailty, but the link between them is understudied. Our objective was to determine the association between ambulatory BP patterns, cognitive function, physical function, and frailty among patients with nondialysis-dependent CKD. Ambulatory BP readings were obtained on 1502 participants of the Chronic Renal Insufficiency Cohort. We evaluated the following exposures: (1) BP patterns (white coat, masked, sustained versus controlled hypertension) and (2) dipping patterns (reverse, extreme, nondippers versus normal dippers). Outcomes included the following: (1) cognitive impairment scores from the Modified Mini Mental Status Examination of <85, <80, and <75 for participants <65, 65-79, and ≥80 years, respectively; (2) physical function, measured by the short physical performance battery (SPPB), with higher scores (0-12) indicating better functioning; and (3) frailty, measured by meeting three or more of the following criteria: slow gait speed, muscle weakness, low physical activity, exhaustion, and unintentional weight loss. Cognitive function and frailty were assessed at the time of ambulatory BP (baseline) and annually thereafter. SPPB was assessed at baseline logistic and linear regression and Cox discrete models assessed the cross-sectional and longitudinal relationship between dipping and BP patterns and outcomes. Mean age of participants was 63±10 years, 56% were male, and 39% were black. At baseline, 129 participants had cognitive impairment, and 275 were frail. Median SPPB score was 9 (interquartile range, 7-10). At baseline, participants with masked hypertension had 0.41 (95% CI, -0.78 to -0.05) lower SPPB scores compared with those with controlled hypertension in the fully adjusted model. Over 4 years of follow-up, 529 participants had incident frailty, and 207 had incident cognitive impairment. After multivariable adjustment, there was no association between BP or dipping patterns and incident frailty or cognitive impairment. In patients with CKD, dipping and BP patterns are not associated with incident or prevalent cognitive impairment or prevalent frailty.

Kidney Clearance of Secretory Solutes Is Associated with Progression of CKD: The CRIC Study.

The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. However, the clinical significance of the kidney's clearance of tubular secretory solutes is uncertain. In this prospective cohort study, we evaluated 3416 participants with CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. We measured plasma and 24-hour urine concentrations of endogenous candidate secretory solutes at baseline, using targeted liquid chromatography-tandem mass spectrometry. The study defined CKD progression by a ≥50% decline in the eGFR, initiation of maintenance dialysis, or kidney transplantation. We used Cox proportional hazards regression to test associations of secretory-solute clearances with CKD progression and mortality, adjusting for eGFR, albuminuria, and other confounding characteristics. Participants in this ancillary study had a mean age of 58 years and 41% were black; the median eGFR was 43 ml/min per 1.73 m2. After adjustment, lower kidney clearances of six solutes-kynurenic acid, pyridoxic acid, indoxyl sulfate, xanthosine, isovalerylglycine, and cinnamoylglycine-were associated with significantly greater risks of CKD progression, with clearance of kynurenic acid, a highly protein-bound solute, having the strongest association. Lower clearances of isovalerylglycine, tiglylglycine, hippurate, and trimethyluric acid were significantly associated with all-cause mortality after adjustment. We found lower kidney clearances of endogenous secretory solutes to be associated with CKD progression and all-cause mortality, independent of eGFR and albuminuria. This suggests that tubular clearance of secretory solutes provides additional information about kidney health beyond measurements of glomerular function alone.

Neighborhood Food Outlet Access and Dietary Intake among Adults with Chronic Kidney Disease: Results from the Chronic Renal Insufficiency Cohort Study

BackgroundHealthy diet is essential in the management of chronic kidney disease (CKD) and preventing related comorbidities. Food outlet access has been studied in the general population; however, the influence of the local food environment on dietary intake among people with CKD has not been evaluated. ObjectivesThis study examined the associations of food outlet density and type of outlets with dietary intake in a multicenter cohort of racially and ethnically diverse patients with CKD. MethodsThe Chronic Renal Insufficiency Cohort Study is a multicenter prospective study of patients with CKD that used a validated food frequency questionnaire to capture dietary intake at the baseline visit. This is a cross-sectional analysis of 2,484 participants recruited in 2003-2006 from seven Chronic Renal Insufficiency Cohort Study centers. Food outlet data were used to construct a count of the number of fast-food restaurants, convenience stores, and grocery stores per 10,000 population for each geocoded census block group. Multivariable linear and logistic regression models were used to evaluate the associations between measures of food outlet availability and dietary factors. ResultsThe proportion of participants living in zero–, low–, and high–food outlet density areas differed by gender, race or ethnicity, and income level. Among male subjects, living in areas with zero or the highest number of outlets was associated with having the highest caloric intakes in multivariable models. Male subjects living in areas with zero outlets consumed the highest levels of sodium and phosphorous. Female subjects living in areas with zero outlets had the lowest average intake of calories, sodium, and phosphorous. Among low-income female subjects, close proximity to more outlets was associated with higher calorie consumption. Among all participants, access to fast-food restaurants was not associated with an unhealthy diet score, and access to grocery stores was not associated with a healthy diet score. ConclusionsAverage caloric and nutrient intakes differed by outlet availability; however, there were no strong associations with type of food outlet. This should be considered when developing food-focused public health policies.

Abstract P514: A Healthy Beverage Score and Risk of Chronic Kidney Disease Progression, Cardiovascular Disease, and All-Cause Mortality in the Chronic Renal Insufficiency Cohort

Background: The association between an overall healthy beverage pattern and chronic disease outcomes is unknown. We created the Healthy Beverage Score (HBS) to characterize the healthfulness of participants’ beverage profiles and examined its association with chronic kidney disease (CKD) progression, cardiovascular disease (CVD), and all-cause mortality among individuals with CKD. Methods: We conducted a prospective analysis of 2,275 participants aged 21-74 years with an estimated glomerular filtration rate (eGFR) between 20 and 70 mL/min/1.73 m 2 from the Chronic Renal Insufficiency Cohort. Diet was assessed using a 124-item food frequency questionnaire at visit 1 (2003-2008). The HBS (7-28) consisted of 7 components. Each component was scored 1-4 based on rank distribution by quartile. Participants were given more points for higher consumption of low-fat milk, coffee and tea, moderate consumption of alcohol, and lower consumption of 100% fruit juice, full-fat milk, artificially-sweetened beverages, and sugar-sweetened beverages. CKD progression, CVD, and all-cause mortality were ascertained through January 2018. We conducted multivariable Cox proportional hazards models. Results: There were 815 cases of CKD progression, 285 cases of CVD, and 725 deaths over a median of 7, 10, and 12 years of follow-up, respectively. Compared with participants in the lowest tertile of the HBS, participants in the highest tertile had a 27% lower risk of CKD progression (hazard ratio, HR: 0.73, 95% confidence interval, CI: 0.61-0.87) ( P -trend&lt;0.001) and 17% lower risk of all-cause mortality (HR: 0.83, 95% CI: 0.69-1.00) ( P -trend=0.05) after adjusting for covariates ( Table ). There was no significant association for CVD comparing tertile 3 with tertile 1 (HR: 0.93, 95% CI: 0.70-1.23) ( P -trend=0.70). Conclusions: A healthier beverage pattern was associated with lower risk of CKD progression and all-cause mortality. Beverage intake may be an important modifiable dietary target in managing outcomes for individuals with CKD.

Abstract P456: The Association Between Clonal Hematopoiesis Of Indeterminate Potential And Inflammatory Biomarkers Among Chronic Kidney Disease Patients

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related disorder associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). Mechanistic studies of CHIP implicate inflammatory pathways underlying this relationship. Although inflammation is a well-established component of chronic kidney disease (CKD), linked to both CKD progression and ASCVD in CKD patients, CHIP has not been investigated in a CKD setting. Objective: To estimate the prevalence of CHIP in patients with CKD and to examine the cross-sectional associations between CHIP and biomarkers that were previously related to CKD progression and ASCVD among CKD patients. Methods: The current study was conducted among 598 Chronic Renal Insufficiency Cohort (CRIC) study participants with whole-exome sequencing data and baseline measures of fibrinogen, interleukin (IL)-6, serum albumin, and tumor necrosis factor-α. CHIP was detected from sequencing data using MuTect2. CHIP was defined as the presence of a somatic hematologic malignancy-associated mutation with a variant allele frequency (VAF) of at least 2%. CHIP was also categorized ordinally by clone size as no CHIP, small CHIP clone (VAF&lt;10%), and large CHIP clone (VAF ≥10%). Ordinal logistic regression was used to test associations of CHIP with each biomarker in age- and multivariable-adjusted models. Multivariable models adjusted for age, sex, ancestry, body mass index, estimated glomerular filtration rate, systolic blood pressure, low-density lipoprotein cholesterol, fasting plasma glucose, and blood pressure, lipid, and glucose lowering medications. Results: CHIP was detected in a total of 28 individuals from the WES study (4.7%). Among those 70 years of age and older, we detected a CHIP prevalence of nearly 16%. As expected, participants with CHIP were older than those without CHIP (mean age: 67 and 58 years, respectively; P&lt;0.0001). Other demographic and clinical variables were similar between groups . Age-adjusted models showed strong associations between CHIP and both fibrinogen and IL-6 with odds ratios of 2.49 (95% CI: 1.09, 5.71) and 2.45 (95% CI: 1.05, 5.72), respectively. After multivariable adjustment, only fibrinogen remained associated with CHIP with an odds ratio of 4.70 (95% CI: 1.69, 13.0). Consistent with these findings, there was a strong dose-dependent association between CHIP clone size and fibrinogen in multivariable adjusted analyses (P for linear trend=0.009). Compared to those without CHIP, odds ratios for higher fibrinogen tertile were 3.0 (95% CI: 0.84, 11.3) and 4.7 (95% CI: 1.29, 16.7) among those with small and large CHIP clone sizes, respectively. Conclusions: CHIP prevalence was higher among CKD patients in the current study compared to previous estimates from the general population. Furthermore, a strong, dose-dependent association between CHIP and fibrinogen was identified.

ACE Inhibitor/Angiotensin Receptor Blocker Use Patterns in Advanced CKD and Risk of Kidney Failure and Death

Rationale & ObjectiveThe use of renin-angiotensin system (RAS) inhibitors is standard of care in people with early to moderate chronic kidney disease (CKD). Less is known regarding the efficacy of RAS inhibitors in very advanced CKD. In this study, we describe patterns of use of RAS inhibitors and associations of these patterns of use with risk for CKD progression and mortality in patients with advanced CKD.Study DesignPropensity-matched cohort study.Settings & ParticipantsWe identified 678 participants who were enrolled in the multicenter Chronic Renal Insufficiency Cohort (CRIC) Study with estimated glomerular filtration rates (eGFRs) < 30 mL/min/1.73 m2 at the baseline visit.ExposureUse of RAS inhibitors within the first year after the baseline visit, characterized by 4 patterns of use: never users, always users, dynamic users, and new users.Outcome(s)Progression to end-stage renal disease (ESRD) and all-cause mortality.Analytical ApproachWe generated propensity scores and matched participants in the always users group with a 1:1 ratio with a participant from the other 3 groups, matching by age, sex, race, diabetes, hypertension, systolic blood pressure, eGFR, urinary protein-creatinine ratio, and serum potassium level. Cox models were used to test the association of patterns of RAS inhibitor use with risk for kidney failure and death.ResultsOf the 678 participants with eGFRs < 30 mL/min/1.73 m2, 57% were identified as always users of RAS inhibitors during the 1 year, 23% as never users, 13% as dynamic users, and 7% as new users. We found no differences in risk for ESRD across patterns of RAS inhibitor use (never users [HR, 1.09; 95% CI, 0.71-1.67], dynamic users [HR, 1.46; 95% CI, 0.83-2.55], new users [HR, 0.78; 95% CI, 0.33-1.84] vs the always users reference group). Similarly, there was no association of patterns of RAS inhibitor use with death (never users [HR, 1.02; CI, 0.74-1.40], dynamic users [HR, 1.23; 95% CI, 0.80-1.90], new users [HR, 1.10; 95% CI, 0.63-1.92] vs always users).LimitationsObservational study.ConclusionsUse of RAS inhibitors in patients with eGFRs < 30 mL/min/1.73 m2 is heterogeneous..We found no difference in risk for progression to ESRD or mortality across patterns of RAS inhibitor use. Further research is required to identify optimal prescribing strategies of RAS inhibitors during advanced stages of CKD.

Association of Prediabetes With CKD Progression and Adverse Cardiovascular Outcomes: An Analysis of the CRIC Study.

Despite our understanding of diabetes as an established risk factor for progressive kidney disease and cardiac complications, the prognostic significance of prediabetes in patients with chronic kidney disease (CKD) remains largely unknown. Participants of the Chronic Renal Insufficiency Cohort (CRIC) were categorized as having normoglycemia, prediabetes, or diabetes according to fasting plasma glucose, glycated hemoglobin A1c (HbA1c), and treatment with antidiabetic drugs at baseline. Unadjusted and adjusted proportional hazards models were fit to estimate the association of prediabetes and diabetes (versus normoglycemia) with: (1) composite renal outcome (end-stage renal disease, 50% decline in estimated glomerular filtration rate to ≤ 15 mL/min/1.73 m2, or doubling of urine protein-to-creatinine ratio to ≥ 0.22 g/g creatinine); (2) composite cardiovascular (CV) outcome (congestive heart failure, myocardial infarction or stroke); and (3) all-cause mortality. Of the 3701 individuals analyzed, 945 were normoglycemic, 847 had prediabetes and 1909 had diabetes. The median follow-up was 7.5 years. Prediabetes was not associated with the composite renal outcome (adjusted hazard ratio [aHR] 1.13; 95% confidence interval [CI], 0.96-1.32; P = 0.14), but was associated with proteinuria progression (aHR 1.23; 95% CI, 1.03-1.47; P = 0.02). Prediabetes was associated with a higher risk of the composite CV outcome (aHR 1.38; 95% CI, 1.05-1.82; P = 0.02) and a trend towards all-cause mortality (aHR 1.28; 95% CI, 0.99-1.66; P = 0.07). Participants with diabetes had an increased risk of the composite renal outcome, the composite CV outcome, and all-cause mortality. In individuals with CKD, prediabetes was not associated with composite renal outcome, but was associated with an increased risk of proteinuria progression and adverse CV outcomes.

Prognostic values of left ventricular mass index in chronic kidney disease patients.

Left ventricular hypertrophy is causally implicated in the high risk of death and heart failure (HF) in chronic kidney disease (CKD) patients. Whether the left ventricular mass index (LVMI) adds meaningful predictive power for mortality and de novo HF to simple risk models has not been tested in the CKD population. We investigated this problem in 1352 CKD patients enrolled in the Chronic Renal Insufficiency Cohort (CRIC). LVMI was measured by echocardiography and the risks for death and HF were estimated by the Study of Heart and Renal Protection (SHARP) score, a well-validated risk score in CKD patients. During a median follow-up of 7.7 years, 326 patients died and 208 had de novo HF. The LVMI and the SHARP score and a cross-validated model for HF (CRIC model) were all significantly (P < 0.001) related to the risk of death and HF. LVMI showed a discriminatory power for death (Harrell's C index 66%) inferior to that of the SHARP score (71%) and the same was true for the risk of HF both in the test (LVMI 72%, CRIC model 79%) and in the validation cohort (LVMI 71%, CRIC model 74%). LVMI increased very little the discriminatory (2-3%) and the risk reclassification power (3.0-4.8%) by the SHARP score and the CRIC model for HF for the same outcomes. In CKD, measurement of LVMI solely for the stratification of risk of death and perhaps for the risk of HF does not provide evident prognostic values in this condition.

Myeloperoxidase and the Risk of CKD Progression, Cardiovascular Disease, and Death in the Chronic Renal Insufficiency Cohort (CRIC) Study

Myeloperoxidase (MPO) catalyzes the formation of reactive nitrogen species and levels are elevated in patients with chronic kidney disease (CKD). Although increased oxidative stress and inflammation are associated with progression of CKD and cardiovascular disease (CVD), relationships between MPO concentration, CKD progression, CVD, and death remain unclear. Prospective cohort. 3,872 participants from the Chronic Renal Insufficiency Cohort (CRIC) who had MPO measured at baseline. Baseline MPO concentration. CKD progression (kidney transplantation, dialysis initiation, or 50% decline in baseline estimated glomerular filtration rate [eGFR] and eGFR≤15mL/min/1.73m2), CVD (heart failure, myocardial infarction, or stroke), and death. Cox proportional hazards models. In adjusted analyses, higher MPO level (per 1-SD increase in log-transformed MPO) was associated with 10% higher risk for CKD progression (adjusted HR, 1.10; 95% CI, 1.01-1.19; P=0.03), 12% higher risk for CVD (adjusted HR, 1.12; 95% CI, 1.03-1.22; P<0.01), and 13% increased risk for death (adjusted HR, 1.13; 95% CI, 1.04-1.22; P<0.01). There was evidence for effect modification of the association of MPO level with CKD progression by baseline eGFR (P interaction=0.02), but not for CVD (P interaction=0.2) or death (P interaction=0.1). In stratified analyses, MPO level (per 1-SD increase in log-transformed MPO) was associated with greater risk for CKD progression among participants with eGFR>45mL/min/1.73m2 (adjusted HR, 1.23; 95% CI, 1.03-1.46; P=0.02) compared with those with eGFR≤45mL/min/1.73m2 (adjusted HR, 1.10; 95% CI, 1.02-1.20; P=0.02). The association of MPO level with CVD and death was no longer significant after adjustment for cardiac biomarkers. Potential residual confounding, lack of repeated measurements of MPO. Higher MPO level was associated with increased risk for CKD progression, but not with CVD and death in patients with CKD from CRIC. Whether therapies aimed at reducing MPO activity can result in improved clinical outcomes is yet to be determined.

Serial Fibroblast Growth Factor 23 Measurements and Risk of Requirement for Kidney Replacement Therapy: The CRIC (Chronic Renal Insufficiency Cohort) Study

Studies using a single measurement of fibroblast growth factor 23 (FGF-23) suggest that elevated FGF-23 levelsare associated with increased risk for requirement for kidney replacement therapy (KRT) in patients with chronic kidney disease. However, the data do not account for changesin FGF-23 levels as kidney disease progresses. Case-cohort study. To evaluate the association between serial FGF-23 levels and risk for requiring KRT, our primary analysis included 1,597 individuals in the Chronic Renal Insufficiency Cohort Study who had up to 5 annual measurements of carboxy-terminal FGF-23. There were 1,135 randomly selected individuals, of whom 266 initiated KRT, and 462 individuals who initiated KRT outside the random subcohort. Serial FGF-23 measurements and FGF-23 trajectory group membership. Incident KRT. To handle time-dependent confounding, our primary analysis of time-updated FGF-23 levels used time-varying inverse probability weighting in a discrete time failure model. To compare our results with prior data, we used baseline and time-updated FGF-23 values in weighted Cox regression models. To examine the association of FGF-23 trajectory subgroups with risk for incident KRT, we used weighted Cox models with FGF-23 trajectory groups derived from group-based trajectory modeling as the exposure. In our primary analysis, the HR for the KRT outcome per 1 SD increase in the mean of natural log-transformed (ln)FGF-23 in the past was 1.94 (95% CI, 1.51-2.49). In weighted Cox models using baseline and time-updated values, elevated FGF-23 level was associated with increased risk for incident KRT (HRs per 1 SD ln[FGF-23] of 1.18 [95% CI, 1.02-1.37] for baseline and 1.66 [95% CI, 1.49-1.86] for time-updated). Membership in the slowly and rapidly increasing FGF-23 trajectory groups was associated with ∼3- and ∼21-fold higher risk for incident KRT compared to membership in the stable FGF-23 trajectory group. Residual confounding and lack of intact FGF-23 values. Increasing FGF-23 levels are independently associated with increased risk for incident KRT.

American Indian Chronic Renal Insufficiency Cohort Study (AI-CRIC Study)

American Indian Chronic Renal Insufficiency Cohort Study (AI-CRIC Study)

High Sensitivity Troponin and Risk of Incident Peripheral Arterial Disease in Chronic Kidney Disease (from the Chronic Renal Insufficiency Cohort [CRIC] Study)

Patients with chronic kidney disease (CKD) are at increased risk for peripheral arterial disease (PAD). A novel biomarker to accurately and reliably predict new onset PAD in high risk patients is needed. High sensitivity troponin (HsTP) is a new assay which allows detection of very low troponin levels with high precision. We sought to explore the association between HsTP and risk of PAD in CKD. The Chronic Renal Insufficiency Cohort (CRIC) is a prospective cohort of 3,939 individuals with mild to moderate CKD using age related criteria for glomerular filtration rate. High sensitivity troponin T was measured at study enrollment. Patients with previous history of PAD or coronary artery disease were excluded. Patients were followed for new-onset adjudicated PAD, and the association between HsTP and incident PAD was examined. A total of 2,909 participants free of PAD and coronary artery disease at enrollment were included in this analysis. Over a mean follow up 7.4 years [interquartile ranges 5.8 to 8.5] years, 79 (2.7%) patients developed PAD. The 3-, 6-, and 9-year incidence of PAD was 1.00%, 2.03%, and 2.72%, respectively. At 9 years, the cumulative rates of PAD increased with HsTP (Quartile 1: 0.3%, Quartile 2: 2.4%, Quartile 3: 3.7%, Quartile 4: 10.7%; p<0.001). After adjusting for clinical risk factors of PAD, patients in the third quartile (Hazards ratio 5.89, 95% confidence interval: 1.31 to 26.47, p = 0.021) and fourth quartile of HsTP (Hazards ratio 10.24, 95% confidence interval 2.23 to 47.08, p = 0.003) had higher risk of PAD compared with lowest quartile of HsTP. HsTP had good discrimination of PAD at 3 years (area under the curve [AUC] 0.76), 6 years (AUC 0.79) and 9 years (AUC 0.80). Addition of HsTP to Framingham risk score improved model discrimination of PAD. In conclusion, in patients with mild-moderate CKD, HsTP levels are associated with and predictive of risk of incident PAD. This association remains significant despite adjustment for traditional PAD risk factors and chronic kidney disease.

Race and Mortality in CKD and Dialysis: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

Few studies have investigated racial disparities in survival among dialysis patients in a manner that considers risk factors and mortality during the phase of kidney disease before maintenance dialysis. Our objective was to explore racial variations in survival among dialysis patients and relate them to racial differences in comorbid conditions and rates of death in the setting of kidney disease not yet requiring dialysis therapy. Retrospective cohort study. 3,288 black and white participants in the Chronic Renal Insufficiency Cohort (CRIC), none of whom were receiving dialysis at enrollment. Race. Mortality. Cox proportional hazards regression was used to examine the association between race and mortality starting at: (1) time of dialysis initiation and (2) entry into the CRIC. During 7.1 years of median follow-up, 678 CRIC participants started dialysis. Starting from the time of dialysis initiation, blacks had lower risk for death (unadjusted HR, 0.67; 95% CI, 0.51-0.87) compared with whites. Starting from baseline CRIC enrollment, the strength of the association between some risk factors and dialysis was notably stronger for whites than blacks. For example, the HR for dialysis onset in the presence (vs absence) of heart failure at CRIC enrollment was 1.30 (95% CI, 1.01-1.68) for blacks versus 2.78 (95% CI, 1.90-4.50) for whites, suggesting differential severity of these risk factors by race. When we included deaths occurring both before and after dialysis, risk for death was higher among blacks (vs whites) starting from CRIC enrollment (HR, 1.41; 95% CI, 1.22-1.64), but this finding was attenuated in adjusted models (HR, 1.08; 95% CI, 0.91-1.28). Residual confounding. The apparent survival advantage among blacks over whites treated with dialysis may be attributed to selected transition of a subset of whites with more severe comorbid conditions onto dialysis.

Physical Symptom Cluster Subgroups in Chronic Kidney Disease.

Symptom burden associated with chronic kidney disease can be debilitating, with a negative effect on patient health-related quality of life. Latent class clustering analysis is an innovative tool for classifying patient symptom experience. The aim of the study was to identify subgroups of patients at greatest risk for high symptom burden, which may facilitate development of patient-centered symptom management interventions. In this cross-sectional analysis, baseline data were analyzed from 3,921 adults enrolled in the Chronic Renal Insufficiency Cohort Study from 2003 to 2008. Latent class cluster modeling using 11 items on the Kidney Disease Quality of Life symptom profile was employed to identify patient subgroups based on similar observed physical symptom response patterns. Multinomial logistic regression models were estimated with demographic variables, lifestyle and clinical variables, and self-reported measures (Kidney Disease Quality of Life physical and mental component summaries and the Beck Depression Inventory). Three symptom-based subgroups were identified, differing in severity (low symptom, moderate symptom, and high symptom). After adjusting for other variables in multinomial logistic regression, membership in the high-symptom subgroup was less likely for non-Hispanic Blacks and men. Other factors associated with membership in the high-symptom subgroup included lower estimated glomerular filtration rate, history of cardiac/cardiovascular disease, higher Beck Depression Inventory scores, and lower Kidney Disease Quality of Life physical and mental component summaries. Three symptom subgroups of patients were identified among patients with mild-to-moderate chronic kidney disease. Several demographic and clinical variables predicted membership in subgroups. Further research is needed to determine if symptom subgroups are stable over time and can be used to predict healthcare utilization and clinical outcomes.

Cardiac and Stress Biomarkers and Chronic Kidney Disease Progression: The CRIC Study.

Increases in cardiac and stress biomarkers may be associated with loss of kidney function through shared mechanisms involving cardiac and kidney injury. We evaluated the associations of cardiac and stress biomarkers [N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), growth differentiation factor 15 (GDF-15), soluble ST-2 (sST-2)] with progression of chronic kidney disease (CKD). We included 3664 participants with CKD from the Chronic Renal Insufficiency Cohort study. All biomarkers were measured at entry. The primary outcome was CKD progression, defined as progression to end-stage renal disease (ESRD) or 50% decline in estimated glomerular filtration rate (eGFR). Cox models tested the association of each biomarker with CKD progression, adjusting for demographics, site, diabetes, cardiovascular disease, eGFR, urine proteinuria, blood pressure, body mass index, cholesterol, medication use, and mineral metabolism. There were 1221 participants who had CKD progression over a median (interquartile range) follow-up of 5.8 (2.4-8.6) years. GDF-15, but not sST2, was significantly associated with an increased risk of CKD progression [hazard ratios (HRs) are per SD increase in log-transformed biomarker]: GDF-15 (HR, 1.50; 95% CI, 1.35-1.67) and sST2 (HR, 1.07; 95% CI, 0.99-1.14). NT-proBNP and hsTnT were also associated with increased risk of CKD progression, but weaker than GDF-15: NT-proBNP (HR, 1.24; 95% CI, 1.13-1.36) and hsTnT (HR, 1.11; 95% CI, 1.01-1.22). Increases in GDF-15, NT-proBNP, and hsTnT are associated with greater risk for CKD progression. These biomarkers may inform mechanisms underlying kidney injury.

Inflammatory Markers and Incidence of Hospitalization With Infection in Chronic Kidney Disease.

Persons with chronic kidney disease (CKD) are at high risk of infection. While low-grade inflammation could impair immune response, it is unknown whether inflammatory markers are associated with infection risk in this clinical population. Using 2003-2013 data from the Chronic Renal Insufficiency Cohort Study (3,597 participants with CKD), we assessed the association of baseline plasma levels of 4 inflammatory markers (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 receptor antagonist (IL-1RA), and transforming growth factor-β (TGF-β)) with incident hospitalization with major infection (pneumonia, urinary tract infection, cellulitis and osteomyelitis, and bacteremia and sepsis). During follow-up (median 7.5 years), 36% (n=1,290) had incident hospitalization with major infection. In multivariable Cox analyses with each inflammatory marker modeled as a restricted cubic spline, higher levels of IL-6 and TNF-α were monotonically associated with increased risk of hospitalization with major infection (for 95th vs. 5th percentile, hazard ratio = 2.11 (95% confidence interval: 1.68, 2.66) for IL-6 and 1.88 (95% confidence interval: 1.51, 2.33) for TNF-α), while corresponding associations for IL-1RA or TGF-β were nonsignificant. Thus, higher plasma levels of IL-6 and TNF-α, but not IL-1RA or TGF-β, were significantly associated with increased risk of hospitalization with major infection. Future studies should investigate whether inflammatory pathways that involve IL-6 and TNF-α increase susceptibility to infection among individuals with CKD.

Serum Calcification Propensity and Clinical Events in CKD.

Patients with CKD are at high risk for cardiovascular disease, ESKD, and mortality. Vascular calcification is one pathway through which cardiovascular disease risks are increased. We hypothesized that a novel measure of serum calcification propensity is associated with cardiovascular disease events, ESKD, and all-cause mortality among patients with CKD stages 2-4. Among 3404 participants from the prospective, longitudinal Chronic Renal Insufficiency Cohort Study, we quantified calcification propensity as the transformation time (T50) from primary to secondary calciprotein particles, with lower T50 corresponding to higher calcification propensity. We used multivariable-adjusted Cox proportional hazards regression models to assess the associations of T50 with risks of adjudicated atherosclerotic cardiovascular disease events (myocardial infarction, stroke, and peripheral artery disease), adjudicated heart failure, ESKD, and mortality. The mean T50 was 313 (SD 79) minutes. Over an average 7.1 (SD 3.1) years of follow-up, we observed 571 atherosclerotic cardiovascular disease events, 633 heart failure events, 887 ESKD events, and 924 deaths. With adjustment for traditional cardiovascular disease risk factors, lower T50 was significantly associated with higher risk of atherosclerotic cardiovascular disease (hazard ratio [HR] per SD lower T50, 1.14; 95% confidence interval [95% CI], 1.05 to 1.25), ESKD within 3 years from baseline (HR per SD lower T50, 1.68; 95% CI, 1.52 to 1.86), and all-cause mortality (HR per SD lower T50, 1.16; 95% CI, 1.09 to 1.24), but not heart failure (HR per SD lower T50, 1.06; 95% CI, 0.97 to 1.15). After adjustment for eGFR and 24-hour urinary protein, T50 was not associated with risks of atherosclerotic cardiovascular disease, ESKD, and mortality. Among patients with CKD stages 2-4, higher serum calcification propensity is associated with atherosclerotic cardiovascular disease events, ESKD, and all-cause mortality, but this association was not independent of kidney function. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_10_28_CJN04710419.mp3.