Comparative CKD risk prediction using homocitrulline and carbamylated albumin: two circulating markers of protein carbamylation.

BACKGROUND: Protein carbamylation, a post-translational protein modification primarily driven by urea, independently associates with adverse clinical outcomes in patients with CKD. Biomarkers used to quantify carbamylation burden have mainly included carbamylated albumin (C-Alb) and homocitrulline (HCit, carbamylated lysine). In this study, we aimed to compare the prognostic utility of these two markers in order to facilitate comparisons of existing studies employing either marker alone, and to inform future carbamylation studies. METHODS: Both serum C-Alb and free HCit levels were assayed from the same timepoint in 1632 individuals with CKD stages 2-4 enrolled in the prospective Chronic Renal Insufficiency Cohort (CRIC) study. Adjusted Cox proportional hazard models were used to assess risks for the outcomes of death (primary) and end stage kidney disease (ESKD) using each marker. C-statistics, net reclassification improvement, and integrated discrimination improvement were used to compare the prognostic value of each marker. RESULTS: Participant demographics included mean (SD) age 59 (11) years; 702 (43%) females; 700 (43%) white. C-Alb and HCit levels were positively correlated with one another (Pearson correlation coefficient 0.64). Higher C-Alb and HCit levels showed similar increased risk of death (e.g., the adjusted hazard ratio [HR] for death in the 4th carbamylation quartile compared to the 1st was 1.90 (95% confidence interval [CI] 1.35-2.66) for C-Alb, and 1.89 [1.27-2.81] for HCit; and on a continuous scale, the adjusted HR for death using C-Alb was 1.24 [1.11 to 1.39] per standard deviation increase, and 1.27 [1.10-1.46] using HCit). Both biomarkers also had similar HRs for ESKD. The C-statistics were similar when adding each carbamylation biomarker to base models (e.g., for mortality models, the C-statistic was 0.725 [0.707-0.743] with C-Alb and 0.725 [0.707-0.743] with HCit, both compared to a base model 0.723). Similarities were also observed for the net reclassification improvement and integrated discrimination improvement metrics. CONCLUSIONS: C-Alb and HCit had similar performance across multiple prognostic assessments. The markers appear readily comparable in CKD epidemiological studies.

Phosphate, fibroblast growth factor 23 and retinopathy in chronic kidney disease: the Chronic Renal Insufficiency Cohort Study.

BACKGROUND: Elevated circulating concentrations of phosphate and fibroblast growth factor 23 (FGF23) contribute to the pathogenesis of cardiovascular disease in chronic kidney disease (CKD). Retinopathy is a common manifestation of microvascular disease in CKD, but its associations with phosphate and FGF23 have not been studied. We tested the hypothesis that higher serum phosphate is associated with more severe retinopathy in individuals with CKD, independent of FGF23 and known risk factors for retinopathy. METHODS: We tested the associations of serum phosphate and plasma FGF23 with retinopathy in a cross-sectional analysis of 1800 participants in the Chronic Renal Insufficiency Cohort Study who underwent fundus photography. Retinopathy severity was graded according to the Early Treatment of Diabetic Retinopathy Severity score, and retinal venous and arterial diameters were measured. RESULTS: Mean estimated glomerular filtration rate (eGFR) was 46.5 ± 15.4 mL/min/1.73 m(2), mean serum phosphate was 3.7 ± 0.6 mg/dl and median plasma C-terminal FGF23 was 133 RU/mL (interquartile range 87.2, 217.8 RU/mL). In multivariable ordinal logistic regression models, higher serum phosphate was associated with greater retinopathy severity independent of hypertension, diabetes, CKD severity and FGF23 [adjusted odds ratio of being in one higher category of retinopathy severity: 1.19 per 1 standard deviation increase; 95% confidence interval (CI) 1.05, 1.36; P = 0.007]. Presence of diabetes or hypertension did not modify the results. Higher serum phosphate was also independently associated with greater retinal venous diameter (multivariable-adjusted 1.70 µm increase per 1 standard deviation increase in phosphate; 95% CI 0.46, 2.93; P = 0.007). FGF23 levels were not independently associated with retinopathy severity or retinal venous diameter, and neither FGF23 nor phosphate was associated with retinal arterial diameter. CONCLUSIONS: Among individuals with moderate-to-severe CKD, higher serum phosphate but not FGF23 was independently associated with more severe retinopathy and microvascular retinal venous dilatation.

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). RESULTS: Compared with participants without diabetes (n = 1,936), those with diabetes (n = 1,820) were more likely to have lower estimated glomerular filtration rate (eGFR), lower serum albumin, and higher urinary protein excretion (all P < 0.001). Unadjusted serum phosphate, PTH, and FGF23 levels were higher and calcium was lower among those with compared with those without diabetes (all P < 0.001). After multivariate adjustment, diabetes remained a significant predictor of serum phosphate, PTH, and FGF23 but not calcium. The eGFR cut point at which 50% of participants met criteria for secondary hyperparathyroidism or elevated FGF23 was higher in participants with diabetes compared with those without (PTH: eGFR 30-39 vs. 20-29, P < 0.001; FGF23: eGFR 50-59 vs. 40-49, P < 0.001). CONCLUSIONS: Disordered mineral metabolism begins earlier in the course of CKD and is more severe among CKD patients with compared with those without diabetes. Future studies should explore mechanisms for these differences and whether they contribute to excess risks of adverse clinical outcomes among diabetic patients with CKD.

Relationship of estimated GFR and coronary artery calcification in the CRIC (Chronic Renal Insufficiency Cohort) Study.

BACKGROUND: Coronary artery calcification (CAC) is associated with increased mortality risk in the general population. Although individuals with chronic kidney disease (CKD) are at markedly increased mortality risk, the incidence, prevalence, and prognosis of CAC in CKD are not well understood. STUDY DESIGN: Cross-sectional observational study. SETTING & PARTICIPANTS: Analysis of 1,908 participants who underwent coronary calcium scanning as part of the multiethnic CRIC (Chronic Renal Insufficiency Cohort) Study. PREDICTOR: Estimated glomerular filtration rate (eGFR) computed using the Modification of Diet in Renal Disease (MDRD) Study equation, stratified by race, sex, and diabetic status. eGFR was treated as a continuous and a categorical variable compared with the reference value of >60 mL/min/1.73 m(2). MEASUREMENTS: CAC detected using computed tomography (CT) using either an Imatron C-300 electron beam computed tomography (CT) scanner or multidetector CT scanner. CAC was computed using Agatston score as a categorical variable. Analyses were performed using ordinal logistic regression. RESULTS: We found a strong and graded relationship between lower eGFR and increasing CAC. In unadjusted models, ORs increased from 1.68 (95% CI, 1.23-2.31) for eGFR of 50-59 mL/min/1.73 m(2) to 2.82 (95% CI, 2.06-3.85) for eGFR <30 mL/min/1.73 m(2). Multivariable adjustment only partially attenuated the results (OR, 1.53; 95% CI, 1.07-2.20) for eGFR <30 mL/min/1.73 m(2). LIMITATIONS: Use of eGFR rather than measured GFR. CONCLUSIONS: We showed a graded relationship between severity of CKD and CAC independent of traditional risk factors. These findings support recent guidelines that state that if vascular calcification is present, it should be considered as a complementary component to be included in the decision making required for individualizing CKD treatment.

Metabolic syndrome, proteinuria, and the risk of progressive CKD in hypertensive African Americans.

BACKGROUND: Chronic kidney disease (CKD) is more likely to progress to kidney failure (end-stage renal disease) in African Americans, although the reasons for this are unclear. Metabolic syndrome is a risk factor for the development of diabetes and cardiovascular disease and recently was linked to incident CKD. The purpose of this study is to examine whether metabolic syndrome is associated with kidney disease progression in hypertensive African Americans. DESIGN & PARTICIPANTS: The current study design is a secondary analysis of the African-American Study of Hypertension and Kidney Disease, a randomized controlled trial of blood pressure goal and agents in hypertensive African Americans with CKD. PREDICTORS: Metabolic syndrome was defined according to the modified National Cholesterol Education Program guidelines. OUTCOMES: Decrease in glomerular filtration rate of 50% or 25 mL/min/1.73 m(2), end-stage renal disease (initiation of dialysis therapy or transplantation), death, or a composite outcome of all 3. RESULTS: 842 subjects were included in this analysis, and 41.7% met criteria for metabolic syndrome. Subjects meeting criteria for metabolic syndrome had greater levels of proteinuria. Cox regression analyses adjusted for age, sex, glomerular filtration rate, and other significant covariates except for proteinuria indicated a 31% increased risk, with a 95% confidence interval of 1.03 to 1.7 (P = 0.03) for time to reach the composite outcome in those with metabolic syndrome. Adjusting for proteinuria, the effect was abated to 16% (95% confidence interval, 0.9 to 1.5), no longer remained significant (P = 0.2), and was unchanged by adjusting randomized treatment group (blood pressure goal or antihypertensive drug). LIMITATIONS: Lack of waist circumference as a better surrogate of abdominal obesity. CONCLUSIONS: In summary, metabolic syndrome is associated with proteinuria in hypertensive African Americans, but is not independently associated with CKD progression.

A comparison of iothalamate-GFR and serum creatinine-based outcomes: acceleration in the rate of GFR decline in the African American Study of Kidney Disease and Hypertension.

In renal clinical trials, both slope-based and time-to-event renal outcomes have been used. These outcomes are typically based on estimates of GFR obtained using creatinine or iothalamate GFR (iGFR). The African American Study of Kidney Disease and Hypertension (AASK) was a trial in 1094 African Americans with hypertensive nephrosclerosis, which examined the effects of two levels of BP control and three antihypertensive regimens. This study compared the effects of the AASK interventions on outcomes based on serum creatinine with corresponding outcomes based on iGFR using 9742 matched pairs of iGFR and serum creatinine measurements. The iGFR-based outcomes included (1) a time-to-event composite outcome including a 50% GFR decline, ESRD, or death; (2) a composite outcome including a 50% GFR decline or ESRD; (3) mean decline in GFR in the first 3 mo after randomization (acute slope); (4) mean decline in GFR starting 3 mo after randomization (chronic slope); and (5) mean decline in GFR from baseline (total slope). The corresponding creatinine-based outcomes were (1) a composite of doubling of serum creatinine, ESRD, or death and (2) a composite of doubling of serum creatinine or ESRD and acute, chronic, and total slopes defined by the mean change in estimated GFR (eGFR), where eGFR was estimated from a regression equation for GFR depending primarily on serum creatinine and developed in AASK enrollees. Mean changes in iGFR and eGFR were also compared under extended models that allowed for the possibility that the rate of GFR decline may change over time during the chronic phase. an apparent acceleration in rate of decline of renal function over time was found. Subtle differences were observed between effects of the interventions on some of the creatinine and iGFR slope-based outcomes, but the main conclusions of the trial were similar for the serum creatinine and iothalamate-based measurements. This has important implications for the design of clinical trials with renal outcomes.